Breast cancer is the second leading cause of cancer death among US women. Inherited mutations in the BRCA1 tumor suppressor gene result in a 50-85% lifetime risk for developing breast cancer and an increased risk for ovarian and prostate cancer. While these germline mutation carriers account for 5% of breast cancer cases, emerging evidence suggests that up to 30% of sporadic breast cancers exhibit epigenetic silencing of BRCA1 by promoter hypermethylation and other mechanisms. These BRCA1 associated tumors are frequently estrogen receptor (ER) negative and often carry mutations of the p53 tumor suppressor protein. The lack of ER renders BRCA1 deficient cancers ineffective targets of hormonal manipulations, therefore making chemotherapy the only treatment option available to patients with metastatic disease. The BRCA1 protein has been implicated in many cellular processes, yet its specific mechanism of tumor suppression remains unclear. BRCA1 plays a role in several DNA repair pathways including nucleotide excision repair (NER). We have demonstrated, by an MTT chemosensitivity assay, that Brca1 deficient murine mammary epithelial cells (MMECs) are 3-fold more sensitive to ultraviolet-C (UV-C) radiation, 10-fold more sensitive to cisplatin, and 25-fold more sensitive to gemcitabine chemotherapy than the isogenic, Brca1 positive parental cell line. In addition, Brca1 deficient cells demonstrate decreased repair of UV-C induced cyclobutane pyrimidine dimers in genomic DNA. Loss of Brca1expression leads to blunted UV-C induced expression of the damaged-DNA binding proteins xeroderma pigmentosum complementation group C (XPC), but not DDB2, which is mutated in xeroderma pigmentosum complementation group E (XPE). These results confirm our earlier findings that Brca1 is involved in global genomic NER, and affects this process through regulation of DNA damage recognition protein gene expression. In addition, the altered chemosensitivity observed in BRCA1 deficient cells raises the possibility that individuals with BRCA1 deficient cancers may benefit from treatment with agents not traditionally used to treat breast cancer.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]