The interaction between 17␤-estradiol and estrogen receptor alpha (ER-␣) plays an important role in breast carcinogenesis and breast cancer treatment. ER-␣ is a critical growth regulatory gene in breast cancer and its expression level is tightly linked to the prognosis and treatment outcomes of breast cancer patients. Loss of ER-␣ expression in breast epithelial cells is critical for breast cancer progression. The underlying molecular mechanisms for this loss, however, are poorly defined. Histone deacetylases (HDACs) are implicated in the alteration of chromatin assembly and tumorigenesis. We show that histone deacetylase 1 (HDAC1) interacts with ER-␣ in vitro and in vivo and suppresses ER-␣ transcription activity. The interaction of HDAC1 with ER-␣ was mediated by the AF-2 and DBD domains of ER-␣. We observed an endogenous interaction of HDAC1 with ER-␣ in breast cancer cells, which was decreased in the presence of estrogen. Interestingly, overexpression of HDAC1 in stable transfected MCF-7 clones induced loss of ER-␣ and significantly increased cell proliferation and colony formation, as compared to the control MCF-7 cells, whereas treatment of stable MCF-7 clones with the HDAC specific inhibitor trichostatin A (TSA) induced re-expression of ER-␣ mRNA and protein. Our findings strongly suggest that HDAC1 affects breast cancer progression by promoting cellular proliferation in association with a reduction in both ER-␣ protein expression and transcriptional activity. Thus, HDAC1 may be a potential target for therapeutic intervention in the treatment of a subset of ER-negative breast cancers.

Germ-line mutations in BRCA1 predispose individuals to breast and ovarian cancers. We observed a novel endogenous association of BRCA1 with Nmi (N-Myc-interacting protein) in breast cancer cells. Nmi was found to interact specifically with BRCA1, both in vitro and in vivo, by binding to two major domains in BRCA1, amino acid residues 298 -683 and 1301-1863. Homodimerization of Nmi enhanced its association with BRCA1. Nmi functioned as an adaptor molecule to recruit c-Myc to a complex containing Nmi⅐c-Myc⅐BRCA1. Because c-Myc can activate transcription of the human telomerase reverse transcriptase gene (hTERT), we addressed the role of BRCA1 and Nmi in modulating c-Myc-induced hTERT promoter activity. Although Nmi or BRCA1 alone had no effect on c-Myc induced hTERT promoter activity, BRCA1 together with Nmi significantly inhibited this c-Myc induced hTERT promoter activity (ϳ75% inhibition). Two mutated forms of BRCA1, a missense (A1708E) and a nonsense (Y1853X) that have been identified in familial breast cancers, associated with Nmi and c-Myc but failed to suppress c-Myc-induced hTERT promoter activity. These results demonstrate a novel pathogenic mechanism whereby mutations in BRCA1, via a novel transcription factor complex containing BRCA1, c-Myc, and Nmi, impair inhibition of c-Myc-induced hTERT promoter activity, which allows sustained activation of telomerase, a key enzyme in carcinogenesis.Germ-line mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. Current evidence demonstrates that mutations in BRCA1 do not directly result in tumor formation but instead cause genetic instability, subjecting cells to a high risk of malignant transformation (1-3). The emerging roles of BRCA1 in regulating transcription, repair of DNA damage, and the cell cycle checkpoint indicate that its functions are broad and complex. The BRCA1 gene encodes an 1863-amino acid (220 K D ) protein that is targeted to the nucleus by nuclear localization sequences (amino acids 503-508 and 606 -615), which interact with the nuclear transport signal receptor (4 -7).

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