Familial Breast Cancer
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There is a growing body of research into genetic factors in breast cancer. In particular about 5% of women with breast cancer have an abnormality of the BRCA1 gene which is localised to chromosome 17q21. In women who inherit this altered gene have a highly increased risk of developing breast cancer, and tend to develop breast cancer at younger age. BRCA1 gene mutation has also been linked to an increased risk for ovarian cancer. Similarly, another gene - BRCA2 which is localised to chromosome 13q12-13 also gives a higher risk of breast and ovarian cancer.

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Breast Cancer
Breast Cancer Genetics (Cancer GeneticsWeb)
BRCA2 gene (13q12.3)
BRCAI gene (17q21)

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Milner R, Wombwell H, Eckersley S, et al.
Validation of the BRCA1 antibody MS110 and the utility of BRCA1 as a patient selection biomarker in immunohistochemical analysis of breast and ovarian tumours.
Virchows Arch. 2013; 462(3):269-79 [PubMed]
BRCA1 protein measurement has previously been evaluated as a potential diagnostic marker without reaching a conclusive recommendation. In this study, we applied current best practice in antibody validation to further characterize MS110, a widely used antibody targeting BRCA1. Antibody specificity was investigated using different biochemical validation techniques. We found that BRCA1 could not be reliably detected using immunoprecipitation and Western blot in endogenously expressing cells. We used immunohistochemistry on formalin-fixed paraffin-embedded cell pellets to establish compatibility with formalin-fixed paraffin-embedded samples. We demonstrated that in transfected cells and cell lines with known genetic BRCA1 status, MS110 successfully detected BRCA1 giving the expected level of staining in immunohistochemistry. Following this, we investigated the use of BRCA1 protein measurement by immunohistochemistry in a cohort of triple negative breast and serous ovarian tumour samples to explore the use of BRCA1 protein measurement by immunohistochemistry for patient stratification. Using MS110 in repeated standardized experiments, on serial sections from a panel of patient samples, results demonstrated considerable run-to-run variability. We concluded that in formalin-fixed tissue samples, MS110 does detect BRCA1; however, using standard methodologies, BRCA1 expression levels in tissue samples is incompatible with the use of this protein as a statistically robust patient selection marker in immunohistochemistry. These results demonstrate the need for further development to deliver BRCA1 protein quantification by immunohistochemistry as a patient stratification marker.


Grotsky DA, Gonzalez-Suarez I, Novell A, et al.
BRCA1 loss activates cathepsin L-mediated degradation of 53BP1 in breast cancer cells.
J Cell Biol. 2013; 200(2):187-202 [PubMed] Article available free on PMC after 21/07/2013
Loss of 53BP1 rescues BRCA1 deficiency and is associated with BRCA1-deficient and triple-negative breast cancers (TNBC) and with resistance to genotoxic drugs. The mechanisms responsible for decreased 53BP1 transcript and protein levels in tumors remain unknown. Here, we demonstrate that BRCA1 loss activates cathepsin L (CTSL)-mediated degradation of 53BP1. Activation of this pathway rescued homologous recombination repair and allowed BRCA1-deficient cells to bypass growth arrest. Importantly, depletion or inhibition of CTSL with vitamin D or specific inhibitors stabilized 53BP1 and increased genomic instability in response to radiation and poly(adenosine diphosphate-ribose) polymerase inhibitors, compromising proliferation. Analysis of human breast tumors identified nuclear CTSL as a positive biomarker for TNBC, which correlated inversely with 53BP1. Importantly, nuclear levels of CTSL, vitamin D receptor, and 53BP1 emerged as a novel triple biomarker signature for stratification of patients with BRCA1-mutated tumors and TNBC, with potential predictive value for drug response. We identify here a novel pathway with prospective relevance for diagnosis and customization of breast cancer therapy.


Turkoz FP, Solak M, Aksoy S, et al.
Association between family history and clinicopathologic characteristics in 1987 breast cancer patients: single institution experience from Turkey.
J BUON. 2012 Oct-Dec; 17(4):649-57 [PubMed]
PURPOSE: To evaluate the clinicopathologic characteristics and survival of patients with family history of breast/ ovarian cancer (FHBOC).
METHODS: In this study with 1987 breast cancer patients, we analyzed their tumor characteristics and outcomes, as well as the total number, degree and age of affected relatives, and their type of cancer. Results were assessed using Pearson chi-square test, Kaplan-Meier method and Cox regression analysis.
RESULTS: 24.1% (n=479) of the patients had FHBOC. Patients with FHBOC were younger (47.7 vs. 49.1 years; p=0.03) and tended to have node-negative breast cancer (45.4 vs. 39.8%; p=0.006). The median overall survival (OS) was shorter in patients with FHBOC with a borderline p-value (p=0.063), compared to patients with no family history. The median OS was shorter in patients who had ≥ 2 relatives with breast cancer (p=0.014), in those having first degree relatives with breast cancer, presenting with metastatic disease (p= 0.020). FHBOC patients with triple negative breast cancer had the highest risk of death (p<0.0001) and recurrence (p<0.0001). Patients who had at least one relative with breast cancer aged ≤ 50 years were also at increased risk of recurrence (p7equals;0.006).
CONCLUSION: Our results suggest that patients with FH7horbar;BOC are younger, tend to have small tumor size, node-negative disease and their survival is shorter compared to patients without family history. This is the first study evaluating the clinicopathologic differences of patients with and without FHBOC in Turkish population.


Cao W, Wang X, Li JC
Hereditary breast cancer in the Han Chinese population.
J Epidemiol. 2013; 23(2):75-84 [PubMed]
Breast cancer is the most common malignancy among women and has a strong genetic background. So far, 13 breast cancer susceptibility genes of high or moderate penetrance have been identified. This review summarizes findings on these genes in Han Chinese. BRCA1 and BRCA2 are the 2 most important susceptibility genes. They have a relatively low mutation rate, and the most frequent sites of mutation are in exon 11. Frameshift mutations are the main type of mutation. Founder mutations may also exist, and BRCA-associated breast cancer has specific clinicopathologic characteristics. TP53 and PALB2 are relatively rare susceptibility genes. The relationship between the other 9 genes and breast cancer has not been fully elucidated. At present, the mutation spectrum for these susceptibility genes is not well understood in the Chinese population, and there are few reports on prognosis and clinical intervention in high-risk populations. Therefore, the true value of genetic counseling for breast cancer has yet to be realized. This article reviews studies of hereditary breast cancer in the Han Chinese population, highlights potential inadequacies, and provides a foundation for genetic counseling for breast cancer in China.


Mokuau N, Braun KL, Daniggelis E
Building family capacity for Native Hawaiian women with breast cancer.
Health Soc Work. 2012; 37(4):216-24 [PubMed]
Native Hawaiian women have the highest breast cancer incidence and mortality rates when compared with other large ethnic groups in Hawai'i. Like other women, they rely on the support of their families as co-survivors. This project explored the feasibility and effects of a culturally tailored educational intervention designed to build family capacity by improving the knowledge and skills of the woman and her family in dealing with breast cancer, particularly in the latter stage of recovery care. Twenty-nine Native Hawaiian women with breast cancer, along with a close family member, were randomly assigned to the intervention (n = 15) or a wait-list control group (n = 14). The authors assessed the knowledge, self-efficacy, and coping skills of women and their family members and the recovery care behaviors of the women at baseline and at four months (after the intervention or control period). The intervention group made significant improvements in self-efficacy and coping; the wait-list control group did not. Evaluation of the intervention suggests that it was well received by participants. This work has relevance for social workers wanting to design and test culturally appropriate interventions for minority groups.


Zhang Q, Zhang Q, Cong H, Zhang X
The ectopic expression of BRCA1 is associated with genesis, progression, and prognosis of breast cancer in young patients.
Diagn Pathol. 2012; 7:181 [PubMed] Article available free on PMC after 21/07/2013
OBJECTIVE: The study is to explore the histopathological features and the molecular marker expression of young women with breast cancers.
METHODS: The pathological data of 367 cases of female breast cancer patients were retrospectively analyzed, focusing on the analysis of young breast cancer incidence trends and the clinical and pathological features.
RESULTS: Compared with elderly breast cancer patients, young women with breast cancers had larger tumor sizes, higher histological grades, and lymph node metastasis rates. The majority of patients were in the PTNM III stage, with the clinical and pathological features of strong invasiveness. The positive expression rate of the BRCA1 protein in the young group was higher than that in the old group. BRCA1 expression was positively correlated with the PTNM stage and axillary lymph node metastasis (P < 0.05).
CONCLUSIONS: The ectopic expression of BRCA1 is associated with the genesis, progression, and prognosis of young breast cancer patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1628000054838044.


Reiner AS, John EM, Brooks JD, et al.
Risk of asynchronous contralateral breast cancer in noncarriers of BRCA1 and BRCA2 mutations with a family history of breast cancer: a report from the Women's Environmental Cancer and Radiation Epidemiology Study.
J Clin Oncol. 2013; 31(4):433-9 [PubMed]
PURPOSE: To fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations.
PATIENTS AND METHODS: From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history-specific 10-year cumulative absolute risks of CBC were estimated.
RESULTS: Family history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%.
CONCLUSION: Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.


Caestecker KW, Van de Walle GR
The role of BRCA1 in DNA double-strand repair: past and present.
Exp Cell Res. 2013; 319(5):575-87 [PubMed]
The breast cancer type 1 susceptibility protein (BRCA1) is involved in several important cellular pathways, including DNA damage repair, chromatin remodeling and checkpoint activation. The BRCA1 tumor suppression function has been attributed to its role in homologous recombination damage repair. In this review, historical facts concerning BRCA1, together with recent research advances regarding our understanding of the BRCA1 interacting proteins that are involved in, homologous recombination (HR) double strand break (DBS) repair and how these interacting proteins maintain chromosomal integrity, are discussed. In addition, this review poses the questions as to what extent HR repair cannot be properly fulfilled when breast cancer related mutations in the BRCA1 gene occur and how the recent and excessive studied poly-ADP ribose polymerase (PARP) inhibiting therapy approach links with the proposed tumor suppression function of the different BRCA1 domains.


Cott Chubiz JE, Lee JM, Gilmore ME, et al.
Cost-effectiveness of alternating magnetic resonance imaging and digital mammography screening in BRCA1 and BRCA2 gene mutation carriers.
Cancer. 2013; 119(6):1266-76 [PubMed] Article available free on PMC after 15/03/2014
BACKGROUND: Current clinical guidelines recommend earlier, more intensive breast cancer screening with both magnetic resonance imaging (MRI) and mammography for women with breast cancer susceptibility gene (BRCA) mutations. Unspecified details of screening schedules are a challenge for implementing guidelines.
METHODS: A Markov Monte Carlo computer model was used to simulate screening in asymptomatic women who were BRCA1 and BRCA2 mutation carriers. Three dual-modality strategies were compared with digital mammography (DM) alone: 1) DM and MRI alternating at 6-month intervals beginning at age 25 years (Alt25), 2) annual MRI beginning at age 25 years with alternating DM added at age 30 years (MRI25/Alt30), and 3) DM and MRI alternating at 6-month intervals beginning at age 30 years (Alt30). Primary outcomes were quality-adjusted life years (QALYs), lifetime costs (in 2010 US dollars), and incremental cost-effectiveness (dollars per QALY gained). Additional outcomes included potential harms of screening, and lifetime costs stratified into component categories (screening and diagnosis, treatment, mortality, and patient time costs).
RESULTS: All 3 dual-modality screening strategies increased QALYs and costs. Alt30 screening had the lowest incremental costs per additional QALY gained (BRCA1, $74,200 per QALY; BRCA2, $215,700 per QALY). False-positive test results increased substantially with dual-modality screening and occurred more frequently in BRCA2 carriers. Downstream savings in both breast cancer treatment and mortality costs were outweighed by increases in up-front screening and diagnosis costs. The results were influenced most by estimates of breast cancer risk and MRI costs.
CONCLUSIONS: Alternating MRI and DM screening at 6-month intervals beginning at age 30 years was identified as a clinically effective approach to applying current guidelines, and was more cost-effective in BRCA1 gene mutation carriers compared with BRCA2 gene mutation carriers.


Werner H, Bruchim I
IGF-1 and BRCA1 signalling pathways in familial cancer.
Lancet Oncol. 2012; 13(12):e537-44 [PubMed]
The insulin-like growth factor (IGF) system has a direct effect on cellular proliferation and survival, and interacts with genetic and environmental factors implicated in causing cancer. Experimental, clinical, and epidemiological evidence show that the IGF signalling pathways are important mediators in the biochemical and molecular chain of events that lead from a phenotypically normal cell to one harbouring neoplastic traits. BRCA1 and BRCA2 have an important role in the development of hereditary and sporadic breast and ovarian cancer. Recent evidence suggests that risk of cancer conferred by BRCA mutations can be modified by genetic and environmental factors, including ambient concentrations of IGF-1 and polymorphisms in IGF system components. This Review addresses interactions between the IGF and BRCA1 signalling pathways, and emphasises the convergence of IGF-1-mediated cell survival, proliferative pathways, and BRCA1-mediated tumour protective pathways. Understanding the complex interactions between these signalling pathways might improve our understanding of basic molecular oncology processes and help to identify new molecular targets, predictive biomarkers, and approaches for optimising cancer therapies.


Kumar P, Mukherjee M, Johnson JP, et al.
Cooperativity of Rb, Brca1, and p53 in malignant breast cancer evolution.
PLoS Genet. 2012; 8(11):e1003027 [PubMed] Article available free on PMC after 15/03/2014
Breast cancers that are "triple-negative" for the clinical markers ESR1, PGR, and HER2 typically belong to the Basal-like molecular subtype. Defective Rb, p53, and Brca1 pathways are each associated with triple-negative and Basal-like subtypes. Our mouse genetic studies demonstrate that the combined inactivation of Rb and p53 pathways is sufficient to suppress the physiological cell death of mammary involution. Furthermore, concomitant inactivation of all three pathways in mammary epithelium has an additive effect on tumor latency and predisposes highly penetrant, metastatic adenocarcinomas. The tumors are poorly differentiated and have histologic features that are common among human Brca1-mutated tumors, including heterogeneous morphology, metaplasia, and necrosis. Gene expression analyses demonstrate that the tumors share attributes of both Basal-like and Claudin-low signatures, two molecular subtypes encompassed by the broader, triple-negative class defined by clinical markers.


Simone B, De Feo E, Nicolotti N, et al.
Methodological quality of English-language genetic guidelines on hereditary breast-cancer screening and management: an evaluation using the AGREE instrument.
BMC Med. 2012; 10:143 [PubMed] Article available free on PMC after 15/03/2014
BACKGROUND: We examined the methodological quality of guidelines on syndromes conferring genetic susceptibility to breast cancer.
METHODS: PubMed, EMBASE, and Google were searched for guidelines published up to October 2010. All guidelines in English were included. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used to assess the quality of the guidelines, and their reported evidence base was evaluated.
RESULTS: Thirteen guidelines were deemed eligible: seven had been developed by independent associations, and the other six had national/state endorsements. Four guidelines performed satisfactorily, achieving a score of greater than 50% in all six AGREE domains. Mean ± SD standardized scores for the six AGREE domains were: 90 ± 9% for 'scope and purpose', 51 ± 18% for 'stakeholder involvement', 55 ± 27% for 'rigour of development', 80 ± 11% for 'clarity and presentation', 37 ± 32% for 'applicability', and 47 ± 38% for 'editorial independence'. Ten of the thirteen guidelines were found to be based on research evidence.
CONCLUSIONS: Given the ethical implications and the high costs of genetic testing for hereditary breast cancer, guidelines on this topic should provide clear and evidence-based recommendations. Our analysis shows that there is scope for improving many aspects of the methodological quality of current guidelines. The AGREE instrument is a useful tool, and could be used profitably by guidelines developers to improve the quality of recommendations.


Vencken PM, Kriege M, Hooning M, et al.
The risk of primary and contralateral breast cancer after ovarian cancer in BRCA1/BRCA2 mutation carriers: Implications for counseling.
Cancer. 2013; 119(5):955-62 [PubMed]
BACKGROUND: The objective of this study was to assess the incidence of primary breast cancer (PBC) and contralateral breast cancer (CBC) in patients who had BRCA1/BRCA2-associated epithelial ovarian cancer (OC).
METHODS: From the database of the Rotterdam Family Cancer Clinic, patients who had BRCA-associated OC without a history of unilateral breast cancer (BC) (at risk of PBC; n = 79) or with a history of unilateral BC (at risk of CBC; n = 37) were selected. The control groups consisted of unaffected BRCA mutation carriers (n = 351) or mutation carriers who had a previous unilateral BC (n = 294), respectively. The risks of PBC and CBC were calculated using the Kaplan-Meier survival method with death considered as a competing risk event.
RESULTS: Women with BRCA-associated OC had lower 2-year, 5-year, and 10-year risks of PBC (3%, 6%, and 11%, respectively) compared with unaffected mutation carriers (6%, 16%, and 28%, respectively; P = .03), although they had a considerably higher mortality rate at similar time points (13%, 33%, and 61%, respectively, vs 1%, 2%, and 2%, respectively; P < .001). In BRCA mutation carriers with a previous unilateral BC, the 2-year, 5-year, and 10-year risks of CBC were nonsignificantly lower in patients with OC than in those without OC (0%, 7%, and 7%, respectively, vs 6%, 16%, and 34%, respectively; P = .06), whereas the mortality rate was higher in patients with OC (19%, 34%, and 55%, respectively, vs 4%, 11%, and 21%, respectively; P < .001).
CONCLUSIONS: Patients with BRCA-associated OC had a lower risk of developing a subsequent PBC or CBC than mutation carriers without OC, whereas the risk of dying from OC was greater than the risk of developing BC. These data may facilitate more tailored counseling for this patient subgroup, although confirmative studies are warranted.


Pinto R, Pilato B, Ottini L, et al.
Different methylation and microRNA expression pattern in male and female familial breast cancer.
J Cell Physiol. 2013; 228(6):1264-9 [PubMed]
Epigenetic regulation, has been very scarcely explored in familial breast cancer (BC). In the present study RASSF1A and RAR beta promoter methylation and miR17, miR21, miR 124, and let-7a expression were investigated to highlight possible differences of epigenetic regulation between male and female familial BC, also in comparison with sporadic BC. These epigenetic alterations were studied in 56 familial BC patients (27 males and 29 females) and in 16 female sporadic cases. RASSF1A resulted more frequently methylated in men than women (76% vs. 28%, respectively, P = 0.0001), while miR17 and let-7a expression frequency was higher in women than in men (miR17: 66% in women vs. 41% in men, P < 0.05; let-7a: 45% in women vs. 15% in men, P = 0.015). RASSF1A methylation affected 27.6% of familial BC while 83% of familial cases showed high expression of the gene (P = 0.025); on the contrary, only 17% of familial BC presented RAR beta methylation and 55% of familial cases overexpressed this gene (P = 0.005). Moreover, miR17, miR21, and let-7a resulted significantly overexpressed in familial compared to sporadic BC. RASSF1A overexpression (86% vs. 65%, P = 0.13) and RAR beta overexpression (57% vs. 32%, P = 0.11) were higher in BRCA1/2 carriers even if not statistical significance was reached. BRCA mutation carriers also demonstrated significant overexpression of: miR17 (93% vs. 35%, P = 0.0001), let-7a (64% vs. 16%, P = 0.002), and of miR21 (100% vs. 65%, P = 0.008). In conclusion, the present data suggest the involvement of RASSF1A in familial male BC, while miR17 and let-7a seem to be implied in familial female BC.


Ray BK, Dhar S, Henry C, et al.
Epigenetic regulation by Z-DNA silencer function controls cancer-associated ADAM-12 expression in breast cancer: cross-talk between MeCP2 and NF1 transcription factor family.
Cancer Res. 2013; 73(2):736-44 [PubMed]
A disintegrin and metalloprotease domain-containing protein 12 (ADAM-12) is upregulated in many human cancers and promotes cancer metastasis. Increased urinary level of ADAM-12 in breast and bladder cancers correlates with disease progression. However, the mechanism of its induction in cancer remains less understood. Previously, we reported a Z-DNA-forming negative regulatory element (NRE) in ADAM-12 that functions as a transcriptional suppressor to maintain a low-level expression of ADAM-12 in most normal cells. We now report here that overexpression of ADAM-12 in triple-negative MDA-MB-231 breast cancer cells and breast cancer tumors is likely due to a marked loss of this Z-DNA-mediated transcriptional suppression function. We show that Z-DNA suppressor operates by interaction with methyl-CpG-binding protein, MeCP2, a prominent epigenetic regulator, and two members of the nuclear factor 1 family of transcription factors, NF1C and NF1X. While this tripartite interaction is highly prevalent in normal breast epithelial cells, both in vitro and in vivo, it is significantly lower in breast cancer cells. Western blot analysis has revealed significant differences in the levels of these 3 proteins between normal mammary epithelial and breast cancer cells. Furthermore, we show, by NRE mutation analysis, that interaction of these proteins with the NRE is necessary for effective suppressor function. Our findings unveil a new epigenetic regulatory process in which Z-DNA/MeCP2/NF1 interaction leads to transcriptional suppression, loss of which results in ADAM-12 overexpression in breast cancer cells.


Moghimi-Dehkordi B, Safaee A, Vahedi M, et al.
Population prevalence of first- and second-degree family history of breast and ovarian cancer.
East Afr J Public Health. 2011; 8(4):275-7 [PubMed]
BACKGROUND: Family cancer history is an important risk factor for common cancers, thus, recognizing pattern of familial cancer can help us to identify individuals who may have higher chance to develop specified cancers.
METHODS: This cross-sectional survey assessed family history of cancer in first- and second degree relatives. Totally, 7,300 persons aged > or = 20 years selected by random sampling from Tehran general population. Age- and sex-specified prevalence of breast and ovarian cancer in respondent's family was calculated.
RESULTS: Of all, 279(4.3%) individuals reported a history of breast or ovarian cancer in their relatives. The prevalence of breast cancer family history was 1.8% among first-degree relatives and 2.5% among second- degree relatives. For ovarian cancer, first- and second-degree prevalence ranged from 0.05 to 0.12%. Those with family history of cancer were more often young and female.
CONCLUSIONS: Overall, the estimates of prevalence presented here are likely to be conservative compared with actual current prevalence because of some limitations. While family history is an important risk factor for common cancers such as breast cancer, recognizing pattern of familial cancer that signify increased risk can help us to identify individuals who may have higher chance to develop specified cancers.


Castilla MÁ, Díaz-Martín J, Sarrió D, et al.
MicroRNA-200 family modulation in distinct breast cancer phenotypes.
PLoS One. 2012; 7(10):e47709 [PubMed] Article available free on PMC after 15/03/2014
The epithelial to mesenchymal transition (EMT) contributes to tumor invasion and metastasis in a variety of cancer types. In human breast cancer, gene expression studies have determined that basal-B/claudin-low and metaplastic cancers exhibit EMT-related characteristics, but the molecular mechanisms underlying this observation are unknown. As the family of miR-200 microRNAs has been shown to regulate EMT in normal tissues and cancer, here we evaluated whether the expression of the miR-200 family (miR-200f) and their epigenetic state correlate with EMT features in human breast carcinomas. We analyzed by qRT-PCR the expression of miR-200f members and various EMT-transcriptional inducers in a series of 70 breast cancers comprising an array of phenotypic subtypes: estrogen receptor positive (ER+), HER2 positive (HER2+), and triple negative (TN), including a subset of metaplastic breast carcinomas (MBCs) with sarcomatous (homologous or heterologous) differentiation. No MBCs with squamous differentiation were included. The DNA methylation status of miR-200f loci in tumor samples were inspected using Sequenom MassArray® MALDI-TOF platform. We also used two non-tumorigenic breast basal cell lines that spontaneously undergo EMT to study the modulation of miR-200f expression during EMT in vitro. We demonstrate that miR-200f is strongly decreased in MBCs compared with other cancer types. TN and HER2+ breast cancers also exhibited lower miR-200f expression than ER+ tumors. Significantly, the decreased miR-200f expression found in MBCs is accompanied by an increase in the expression levels of EMT-transcriptional inducers, and hypermethylation of the miR-200c-141 locus. Similar to tumor samples, we demonstrated that downregulation of miR-200f and hypermethylation of the miR-200c-141 locus, together with upregulation of EMT-transcriptional inducers also occur in an in vitro cellular model of spontaneous EMT. Thus, the expression and methylation status of miR-200f could be used as hypothetical biomarkers to assess the occurrence of EMT in breast cancer.


Pern F, Bogdanova N, Schürmann P, et al.
Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital-based series of German patients with triple-negative breast cancer.
PLoS One. 2012; 7(10):e47993 [PubMed] Article available free on PMC after 15/03/2014
Triple-negative breast cancer (TNBC) is an aggressive form of breast carcinoma with a poor prognosis. Recent evidence suggests that some patients with TNBC harbour germ-line mutations in DNA repair genes which may render their tumours susceptible to novel therapies such as treatment with PARP inhibitors. In the present study, we have investigated a hospital-based series of 40 German patients with TNBC for the presence of germ-line mutations in BRCA1, BRCA2, PALB2, and BRD7 genes. Microfluidic array PCR and next-generation sequencing was used for BRCA1 and BRCA2 analysis while conventional high-resolution melting and Sanger sequencing was applied to study the coding regions of PALB2 and BRD7, respectively. Truncating mutations in BRCA1 were found in six patients, and truncating mutations in BRCA2 and PALB2 were detected in one patient each, whereas no truncating mutation was identified in BRD7. One patient was a double heterozygote for the PALB2 mutation, c.758insT, and a BRCA1 mutation, c.927delA. Our results confirm in a hospital-based setting that a substantial proportion of German TNBC patients (17.5%) harbour germ-line mutations in genes involved in homology-directed DNA repair, with a preponderance of BRCA1 mutations. Triple-negative breast cancer should be considered as an additional criterion for future genetic counselling and diagnostic sequencing.


Sawyer S, Mitchell G, McKinley J, et al.
A role for common genomic variants in the assessment of familial breast cancer.
J Clin Oncol. 2012; 30(35):4330-6 [PubMed]
PURPOSE: Genome-wide association studies have identified common genomic variants associated with increased susceptibility to breast cancer. In the general population, the risk associated with these known variants seems insufficient to inform clinical management. Their contribution to the development of familial breast cancer is less clear.
PATIENTS AND METHODS: We studied 1,143 women with breast cancer who had completed BRCA1 and BRCA2 mutation screening as a result of a high risk for hereditary breast cancer. Genotyping of 22 breast cancer-associated genomic variants was performed. A polygenic risk score (PRS), calculated as the sum of the log odds ratios for each allele, was compared with the same metric in 892 controls from the Australian Ovarian Cancer Study. The clinical features associated with the high and low ends of the polygenic risk distribution were compared.
RESULTS: Women affected by familial breast cancer had a highly significant excess of risk alleles compared with controls (P = 1.0 × 10(-16)). Polygenic risk (measured by the PRS) was greater in women who tested negative for a BRCA1 or BRCA2 mutation compared with mutation carriers (P = 2.3 × 10(-6)). Non-BRCA1/2 women in the top quartile of the polygenic risk distribution were more likely to have had early-onset breast cancer (< 30 years of age, odds ratio [OR]= 3.37, P = .03) and had a higher rate of second breast cancer (OR 1.96, P = .02) compared with women with low polygenic risk.
CONCLUSION: Genetic testing for common risk variants in women undergoing assessment for familial breast cancer may identify a distinct group of high-risk women in whom the role of risk-reducing interventions should be explored.


Yakovlev VA
Nitric oxide-dependent downregulation of BRCA1 expression promotes genetic instability.
Cancer Res. 2013; 73(2):706-15 [PubMed] Article available free on PMC after 15/01/2014
Elevated levels of nitric oxide (NO) and reactive nitrogen species (RNS) may link inflammation to the initiation, promotion, and progression of cancer. Traditionally, this link has been thought to be mediated by the effects of NO/RNS in generating DNA damage. However, this damage also stimulates DNA repair responses with subsequent blocks to cell proliferation and apoptosis, thereby preventing accumulation of NO/RNS-generated mutations. In addressing this conundrum, I describe here an alternative mechanism for understanding mutagenesis by NO/RNS. Moderate NO/RNS concentrations stimulated mutagenesis not directly by generating DNA damage but indirectly by modifying the activities of DNA repair and genome stability factors without affecting cell proliferation. NO/RNS at concentrations physiologically relevant to inflammation stimulated PP2A activity, leading to dephosphorylation of RBL2, its accumulation in the nucleus, and formation of RBL2/E2F4 complexes. RBL2/E2F4 formation in turn led to a shift in BRCA1 promoter occupancy from complexes containing activator E2F1 to complexes containing repressor E2F4, downregulating BRCA1 expression. By inhibiting BRCA1 expression, NO/RNS thereby reduces the ability of cells to repair DNA double-strand breaks through homologous recombination repair, increasing the involvement of error-prone nonhomologous end joining (NHEJ). In summary, NO/RNS stimulates genetic instability by inhibiting BRCA1 expression and shifting DNA repair from high fidelity to error-prone mechanisms.


Lu Y, Li J, Cheng D, et al.
The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation.
J Biol Chem. 2012; 287(49):41014-22 [PubMed] Article available free on PMC after 30/11/2013
BRCA1 mutations account for a significant proportion of familial breast and ovarian cancers. In addition, reduced BRCA1 protein is associated with sporadic cancer cases in these tissues. At the cellular level, BRCA1 plays a critical role in multiple cellular functions such as DNA repair and cell cycle checkpoint control. Its protein level is regulated in a cell cycle-dependent manner. However, regulation of BRCA1 protein stability is not fully understood. Our earlier study showed that the amino terminus of BRCA1 harbors a degron sequence that is sufficient and necessary for conferring BRCA1 degradation. In the current study, we used mass spectrometry to identify Skp1 that regulates BRCA1 protein stability. Small interfering RNA screening that targets all human F-box proteins uncovered FBXO44 as an important protein that influences BRCA1 protein level. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. Furthermore, the N terminus of BRCA1 mediates the interaction between BRCA1 and FBXO44. Overexpression of SCF(FBXO44) reduces BRCA1 protein level. Taken together, our work strongly suggests that SCF(FBXO44) is an E3 ubiquitin ligase responsible for BRCA1 degradation. In addition, FBXO44 expression pattern in breast carcinomas suggests that SCF(FBXO44)-mediated BRCA1 degradation might contribute to sporadic breast tumor development.


Haber G, Ahmed NU, Pekovic V
Family history of cancer and its association with breast cancer risk perception and repeat mammography.
Am J Public Health. 2012; 102(12):2322-9 [PubMed]
OBJECTIVES: We examined the strength of association between family history of breast cancer and family history of other cancers with breast cancer risk perception and repeat mammography.
METHODS: The sample included 6706 women, aged 46 to 74 years, with no breast cancer history. Multinomial logistic regression assessed the association between family history of cancer and breast cancer risk perception. Structural equation modeling estimated the relationship between family history of cancer and repeat mammography.
RESULTS: Breast cancer risk perception was strongly associated with family history of breast cancer in the mother or mother and sister (odds ratio [OR] = 32.15; P < .001); family history of breast cancer in the sister, daughter, or male first-degree relative (OR = 6.6-8.4; P < .001); and maternal history of other cancers (OR = 1.38-2.73; P < .001). For repeat mammography, women with maternal history of breast cancer had a mean increase of 0.50 more mammograms in the past 6 years compared with women without maternal history of breast cancer (P < .001).
CONCLUSIONS: Breast cancer risk perception was associated with the type of cancer found in first-degree relatives and with the person's relationship to the family member with cancer. Family history of breast cancer affected repeat mammography behavior.


Stefansson OA, Villanueva A, Vidal A, et al.
BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer.
Epigenetics. 2012; 7(11):1225-9 [PubMed] Article available free on PMC after 30/11/2013
Germline mutations in the BRCA1 or BRCA2 genes are associated with an increased risk of breast and ovarian cancer development. Both genes are involved in DNA repair, and tumors harboring genetic defects in them are thought to be more sensitive to DNA-damaging agents used in chemotherapy. However, as only a minority of breast and ovarian cancer patients carry BRCA1 or BRCA2 mutations, few patients are likely to benefit from these pharmacogenetic biomarkers. Herein, we show that, in cancer cell lines and xenografted tumors, BRCA1 CpG island promoter hypermethylation-associated silencing also predicts enhanced sensitivity to platinum-derived drugs to the same extent as BRCA1 mutations. Most importantly, BRCA1 hypermethylation proves to be a predictor of longer time to relapse and improved overall survival in ovarian cancer patients undergoing chemotherapy with cisplatin.


Muñoz MC, Laulier C, Gunn A, et al.
RING finger nuclear factor RNF168 is important for defects in homologous recombination caused by loss of the breast cancer susceptibility factor BRCA1.
J Biol Chem. 2012; 287(48):40618-28 [PubMed] Article available free on PMC after 23/11/2013
BACKGROUND: RNF168 promotes chromosomal break localization of 53BP1 and BRCA1; 53BP1 loss rescues homologous recombination (HR) in BRCA1-deficient cells.
RESULTS: RNF168 depletion suppresses HR defects caused by BRCA1 silencing; RNF168 influences HR similarly to 53BP1.
CONCLUSION: RNF168 is important for HR defects caused by BRCA1 loss.
SIGNIFICANCE: Although RNF168 promotes BRCA1 and 53BP1 localization to chromosomal breaks, RNF168 affects HR similarly to 53BP1. The RING finger nuclear factor RNF168 is required for recruitment of several DNA damage response factors to double strand breaks (DSBs), including 53BP1 and BRCA1. Because 53BP1 and BRCA1 function antagonistically during the DSB repair pathway homologous recombination (HR), the influence of RNF168 on HR has been unclear. We report that RNF168 depletion causes an elevated frequency of two distinct HR pathways (homology-directed repair and single strand annealing), suppresses defects in HR caused by BRCA1 silencing, but does not suppress HR defects caused by disruption of CtIP, RAD50, BRCA2, or RAD51. Furthermore, RNF168-depleted cells can form ionizing radiation-induced foci of the recombinase RAD51 without forming BRCA1 ionizing radiation-induced foci, indicating that this loss of BRCA1 recruitment to DSBs does not reflect a loss of function during HR. Additionally, we find that RNF168 and 53BP1 have a similar influence on HR. We suggest that RNF168 is important for HR defects caused by BRCA1 loss.


Margalit O, Wang D, Dubois RN
PPARγ agonists target aromatase via both PGE2 and BRCA1.
Cancer Prev Res (Phila). 2012; 5(10):1169-72 [PubMed] Article available free on PMC after 01/10/2013
Obesity is a well-recognized risk factor for postmenopausal breast cancer. Although the underlying mechanisms are not clearly defined, aromatase is thought to play a pivotal role in connecting obesity-associated inflammation with postmenopausal breast cancer. It has been well established that both the proinflammatory prostaglandin E(2) (PGE(2)) and the BRCA1 tumor-suppressor gene regulate aromatase expression. In this issue of the journal (beginning on p. 1183), Subbaramaiah and colleagues improve our understanding of the molecular mechanisms by which PPARγ inhibits aromatase expression. They found that pioglitazone, a PPARγ agonist, inhibited aromatase expression by inhibition of PGE(2) signaling and upregulation of BRCA1. Their findings provide potential targets for preventing or treating obesity-related breast cancer.


Pal T, Vadaparampil ST
Genetic risk assessments in individuals at high risk for inherited breast cancer in the breast oncology care setting.
Cancer Control. 2012; 19(4):255-66 [PubMed]
BACKGROUND: It has become increasingly common to consider BRCA mutation status when determining optimal cancer risk management and treatment options in order to improve patient outcomes. Knowledge about the risk for hereditary cancer at or as close as possible to the time of diagnosis allows patients access to the most risk reduction options available.
METHODS: This paper illustrates the role of genetic risk assessment for hereditary breast cancer, using hereditary breast and ovarian cancer (HBOC) syndrome as a model due to germline mutations in the BRCA1 and BRCA2. Specifically, the value of genetic counseling and testing for HBOC across the cancer prevention and control continuum is outlined as it pertains to breast cancer.
RESULTS: In recognition of the importance of risk assessment for hereditary breast cancer, leading health professional organizations have developed specific guidelines and recommendations to providers for identification of women at increased risk for carrying a BRCA mutation.
CONCLUSIONS: Institutional efforts specific to genetic counseling and testing have resulted in the implementation of a model driven by physician recommendation as a referral system for high-risk breast cancer patients. Establishing an infrastructure to support research, education, and outreach initiatives focused on BRCA genetic counseling and testing will provide information that can improve the delivery of cancer genetics services.


Michils G, Hollants S, Dehaspe L, et al.
Molecular analysis of the breast cancer genes BRCA1 and BRCA2 using amplicon-based massive parallel pyrosequencing.
J Mol Diagn. 2012; 14(6):623-30 [PubMed]
The aim of this study was to implement the massively parallel sequencing technology for diagnostic applications. We evaluated an amplicon-based method for the analysis of the BRCA1 and BRCA2 genes on the Roche 454 GS-FLX sequencer, to identify disease-causing mutations in breast and/or ovarian cancer patients. A first evaluation relied on the analysis of DNA fragments containing known mutations. Secondly, the entire coding regions of the BRCA1 and BRCA2 genes were interrogated in more than 400 patient samples, using a multiplex PCR-based assay. Variants were filtered on the basis of their frequency (20%) and sequencing depth (>25×). Special attention was given to sequencing accuracy in homopolymers. In the initial evaluation, all known heterozygous mutations were detected. The percentage of mutant reads ranged from 22% to 62%. For the multiplex assay, 95% sensitivity and 91% specificity were obtained. In addition, we were able to reliably distinguish mutations from noise through the analysis of the raw signal intensities in homopolymers. This work presents an evaluation of the next-generation sequencing for use in diagnostics, based on a relatively high number of samples and experiments. We anticipate that the technique would further improve, and would allow reducing the costs per analysis and the turn-around time, to benefit patients who undergo BRCA molecular testing.


Svetina M, Nastran K
Family relationships and post-traumatic growth in breast cancer patients.
Psychiatr Danub. 2012; 24(3):298-306 [PubMed]
BACKGROUND: Post-traumatic growth (PTG) refers to the process of attributing meaning to traumatic events and positive changes in life after facing trauma. A number of studies have already demonstrated that demographic- and coping-approaches related variables predict PTG, yet little is known about whether PTG may be predicted by family processes such as flexibility, cohesion, communication and satisfaction. The main purpose of the study therefore was to determine whether family-related factors predict PTG above and beyond demographic variables and coping related processes.
SUBJECTS AND METHODS: The study included 190 women, breast-cancer patients, aged 31 to 83 years. Their educational level was representative of the educational level in the population of this age range. The Participants were members of the Oncology Patients Society. Post traumatic growth index, FACES-IV - family relationships scale, coping response inventory, demographic, and illness-related questionnaires were administered after informed consent was obtained. The PTG index was used as an outcome measure.
RESULTS: Congruent with previous findings, analyses yielded weak correlations between demographic- and illness-related variables, and PTG. Also congruent with previous findings, approach related coping strategies were found to predict PTG, R squared =0.16, p<0.001. In addition to previous findings, family related factors predicted unique proportion of variance on PTG, p<0.05, with communication having positive and satisfaction negative load on PTG.
CONCLUSIONS: Results showed that family related factors predicted PTG above and beyond coping-related strategies and demographics. Communication, however, seems to mediate the association between satisfaction and PTG. Theoretical concerns and practical implications are discussed.


Fakkert IE, Mourits MJ, Jansen L, et al.
Breast Cancer Incidence After Risk-Reducing Salpingo-Oophorectomy in BRCA1 and BRCA2 Mutation Carriers.
Cancer Prev Res (Phila). 2012; 5(11):1291-7 [PubMed]
Premenopausal risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers effectively reduces ovarian cancer risk, but also reduces breast cancer risk. Breast cancer risk reductions up to 50% have been reported for both BRCA1 and BRCA2 mutation carriers, but recent prospective studies were not able to reproduce this finding for BRCA1 mutation carriers. Breast cancer incidence after RRSO was assessed in a consecutive series of 104 BRCA1 and 58 BRCA2 mutation carriers. On the basis of data from our own centre, and assuming a 50% risk reduction through RRSO at premenopausal age, we expected to find 8 breast cancers (range 6-10) in this population for the reported screening period (532 women-years). In 162 carriers with a median age of 41 years at RRSO, 13 incident breast cancers were diagnosed. In BRCA1 mutation carriers, 12 incident breast cancers were found compared with 5 (range 3-6) expected and in BRCA2 mutation carriers 1 breast cancer was found compared with 3 (range 2-5) expected. Breast cancer incidence after premenopausal RRSO is still high, especially in BRCA1 mutation carriers. Previously reported breast cancer risk reductions up to 50% were not confirmed. As a consequence, continued intensive screening for breast cancer is warranted in BRCA1 and BRCA2 mutation carriers after RRSO.


Kwong A, Ng EK, Wong CL, et al.
Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis.
PLoS One. 2012; 7(9):e43994 [PubMed] Article available free on PMC after 01/10/2013
BACKGROUND: Ethnic variations in breast cancer epidemiology and genetics have necessitated investigation of the spectra of BRCA1 and BRCA2 mutations in different populations. Knowledge of BRCA mutations in Chinese populations is still largely unknown. We conducted a multi-center study to characterize the spectra of BRCA mutations in Chinese breast and ovarian cancer patients from Southern China.
METHODOLOGY/PRINCIPAL FINDINGS: A total of 651 clinically high-risk breast and/or ovarian cancer patients were recruited from the Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2011. Comprehensive BRCA1 and BRCA2 mutation screening was performed using bi-directional sequencing of all coding exons of BRCA1 and BRCA2. Sequencing results were confirmed by in-house developed full high resolution DNA melting (HRM) analysis. Among the 451 probands analyzed, 69 (15.3%) deleterious BRCA mutations were identified, comprising 29 in BRCA1 and 40 in BRCA2. The four recurrent BRCA1 mutations (c.470_471delCT, c.3342_3345delAGAA, c.5406+1_5406+3delGTA and c.981_982delAT) accounted for 34.5% (10/29) of all BRCA1 mutations in this cohort. The four recurrent BRCA2 mutations (c.2808_2811delACAA, c.3109C>T, c.7436_7805del370 and c.9097_9098insA) accounted for 40% (16/40) of all BRCA2 mutations. Haplotype analysis was performed to confirm 1 BRCA1 and 3 BRCA2 mutations are putative founder mutations. Rapid HRM mutation screening for a panel of the founder mutations were developed and validated.
CONCLUSION: In this study, our findings suggest that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Southern Chinese population. Knowing the spectrum and frequency of the founder mutations in this population will assist in the development of a cost-effective rapid screening assay, which in turn facilitates genetic counseling and testing for the purpose of cancer risk assessment.


This page last updated: 22nd May 2013
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