Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A, Deng CXConditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet 22: 37-43

Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Genetics (Impact Factor: 29.35). 06/1999; 22(1):37-43. DOI: 10.1038/8743
Source: PubMed


Cre-mediated excision of exon 11 of the breast-tumour suppressor gene Brca1 in mouse mammary epithelial cells causes increased apoptosis and abnormal ductal development. Mammary tumour formation occurs after long latency and is associated with genetic instability characterized by aneuploidy, chromosomal rearrangements or alteration of Trp53 (encoding p53) transcription. To directly test the role of p53 in Brca1-associated tumorigenesis, we introduced a Trp53-null allele into mice with mammary epithelium-specific inactivation of Brca1. The loss of p53 accelerated the formation of mammary tumours in these females. Our results demonstrate that disruption of Brca1 causes genetic instability and triggers further alterations, including the inactivation of p53, that lead to tumour formation.

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Available from: Lothar Hennighausen, Jan 11, 2014
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    • "Assignment of a specific mutation as a true predisposition to a disease family requires solid phenotypic evidence from in vitro analysis, cell line tests, search of the literature, bioinformatics data analysis, and animal models. This is best evidenced by determining the BRCA1 germline mutations as genetic predispositions in breast cancer, in which the definitive conclusion for its contribution to breast cancer is based on the mouse models showing development of breast cancer with the germline mutated BRCA1[42]. Our current study aims to provide evidence that the BRCAx disease families are enriched with germline damaging mutations, such that focusing on each disease family will be required to determine the genetic predisposition in each family. Indeed, even under strict mapping conditions, large numbers of mutations have been detected in each disease family and probands. "
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    ABSTRACT: Background Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide high probability to identify the genetic predisposition for each family. Methods In this study, we tested genetic predispositions by analyzing the family-specific variants in familial breast cancer. Using exome sequencing, we analyzed three families and 22 probands with BRCAx (BRCA-negative) familial breast cancer. Results We observed the presence of family-specific, novel, deleterious germline variants in each family. Of the germline variants identified, many were shared between the disease-affected family members of the same family but not found in different families, which have their own specific variants. Certain variants are putative deleterious genetic predispositions damaging functionally important genes involved in DNA replication and damaging repair, tumor suppression, signal transduction, and phosphorylation. Conclusions Our study demonstrates that the predispositions for many BRCAx familial breast cancer families can lie in each disease family. The application of a family-focused approach has the potential to detect many new predispositions.
    BMC Cancer 06/2014; 14(1):470. DOI:10.1186/1471-2407-14-470 · 3.36 Impact Factor
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    • "Of the three distinct classes of “simple”, “amplifier” and “complex” DNA copy-number alterations defined for breast cancer, BRCA1+ breast cancer fits within the “complex” class [13]. Conditional Brca1 knockout in the mouse model results in breast tumor formation after a long latency, changes in the centrosomes, chromosomal gain and loss in specific segments orthologous to the genetic loci mutated in human breast cancer [14-16]. Data from these studies indicate that many types of genetic defects in the genome are caused by BRCA1+ induced genome instability. "
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    ABSTRACT: Background BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known about somatic genome instability in breast cancer cells but not germline genome instability. Methods Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six breast cancer-affected and two breast cancer unaffected members. Results We identified 23 deleterious mutations in the breast cancer-affected family members, which are absent in the unaffected members. Multiple mutations damaged functionally important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations were germline mutation inherited from the ancestor(s) while only a few were somatic mutation generated de novo. Conclusion Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast cells.
    BMC Cancer 05/2014; 14(1):342. DOI:10.1186/1471-2407-14-342 · 3.36 Impact Factor
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    • "Therefore, most of BRCA1 mutation carriers have one allele of normal functional Brca1 gene expression. BRCA1 mutation carriers have much higher rate of developing cancer in hormone responsive tissues such as breast, ovary and prostate by comparing to other tissues 14-17. Intriguingly, hormone therapy is not feasible to treat BRCA1 mutation related breast cancer because it generally shows basal-like characters and is triple negative. "
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    ABSTRACT: BRCA1 mainly acts as a tumor suppressor and BRCA1 mutation correlates with increased cancer risk. Although it is well recognized that BRCA1 related tumorigenesis is mainly caused by the increased DNA damage and decreased genome stability, it is not clear that why BRCA1 related patients have higher risk for cancer development mainly in estrogen responsive tissues such as breast and ovary. Recent studies suggested that BRCA1 and E-ER (estrogen and estrogen receptor) signaling synergistically regulate the mammary epithelial cell proliferation and differentiation. In this current presentation, we reviewed the correlation between mammary gland epithelial cell transformation and the status of BRCA1 and ER. Then the mechanisms of BRCA1 and E-ER interaction at both gene transcription level and protein-protein interaction level are discussed. Furthermore, the tumorigenic mechanisms are discussed by focusing on the synergistic effect of BRCA1 and E-ER on cell metabolism, ROS management, and antioxidant activity in mammary gland epithelial cells. Also, the possibility of cell de-differentiation promoted by coordinated effect between BRCA1 mutation and E-ER signal is explored. Together, the currently available evidences suggest that BRCA1 mutation and E-ER signal together, contribute to breast tumorigenesis by providing the metabolic support for cancer cell growth and even may directly be involved in promoting the de-differentiation of cancer-prone epithelial cells.
    International journal of biological sciences 05/2014; 10(5):563-573. DOI:10.7150/ijbs.8579 · 4.51 Impact Factor
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