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CURATOR
A pinboard by
Judit Jimenez-Sainz

Postdoc, Yale Medical School

PINBOARD SUMMARY

BRCA2 DNA repair and Breast and Ovarian Cancer progression

Ovarian cancer is the fifth leading cause of cancer death among U.S women accounting for more deaths than any other cancer of the female reproductive system, and about 5% of women in US will develop lethal ovarian cancer during their lifetime. BRCA2 (Breast Cancer Susceptibility Gene 2) was originally identified as one of two genes responsible for familial inherited breast and ovarian cancer. Women who inherit a mutant copy of BRCA2 have up to an 80% lifetime risk of developing breast cancer. BRCA2 is directly involved in a cellular process termed DNA repair to maintain genome integrity. Malfunctions in DNA repair proteins, which are quality control inspectors, can lead to a process termed “genomic instability” whereby mutations throughout the genome are accumulated at an accelerated rate. If these mutations lie in specific genes that control cellular division or death, a cell may acquire the capability to seed a tumor. The BRCA2 protein protects against this process by repairing damaged DNA and suppressing the accumulation of mutations through a specialized process called homologous recombination. The clinical options for preventing future cancers in BRCA2 mutation carriers involve prophylactic bilateral mastectomy and salpingo-oophorectomy, major surgical interventions that may be emotionally difficult for patients. The recent advent of PARP inhibitors as a synthetic lethal strategy to target BRCA mutant tumors while promising, may not have the efficacy that was initially expected and resistance to this therapy is already emerging in some patients. We still lack a basic, molecular understanding of how breast tumors are initiated in BRCA2 carriers which can help to early diagnosis, as well as how tumors acquire resistance to our current standard-of-care treatments. Elucidation of the underlying BRCA2 biology may unveil pathways or genes that could lead to initial prevention strategies targeting the early steps of tumor formation for these patients. Therefore, my main objective in this study is to dissect the molecular changes that drive ovarian tumor initiation in the setting of BRCA2 dysfunction. In order to address this issue, we have created a human fallopian tube cell system where we can regulate the levels of BRCA2 mimicking the acute loss of BRCA2 function that occurs in BRCA2 carriers. We have validated that our system effectively controls the levels of BRCA2 and we have confirmed the hallmarks of BRCA2 loss in fallopian tube cells.

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