Expression profiling of T24 cells revealed that 17 out of 313 human miRNAs were upregulated more than 3-fold by simultaneous treatment with the chromatin-modifying drugs 5-aza-2'-deoxycytidine and 4-phenylbutyric acid. One of these, miR-127, is embedded in a CpG island and is highly induced from its own promoter after treatment. miR-127 is usually expressed as part of a miRNA cluster in normal cells but not in cancer cells, suggesting that it is subject to epigenetic silencing. In addition, the proto-oncogene BCL6, a potential target of miR-127, was translationally downregulated after treatment. These results suggest that DNA demethylation and histone deacetylase inhibition can activate expression of miRNAs that may act as tumor suppressors.

An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that this region is a transcriptional enhancer, that the risk region physically interacts with the MYC proto-oncogene, and that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2). These data provide strong support for a biological mechanism underlying this non-protein coding risk variant.

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There is emerging evidence that the balance between estrogen receptor-A (ERA) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed AR status in a cohort of 215 invasive ductal breast carcinomas. AR and ERA were coexpressed in the majority (80-90%) of breast tumor cells. KaplanMeier product limit analysis and multivariate Cox regression showed that AR is an independent prognostic factor in ERApositive disease, with a low level of AR (less than median of 75% positive cells) conferring a 4.6-fold increased risk of cancer-related death (P = 0.002). Consistent with a role for AR in breast cancer outcome, AR potently inhibited ERA transactivation activity and 17B-estradiol-stimulated growth of breast cancer cells. Transfection of MDA-MB-231 breast cancer cells with either functionally impaired AR variants or the DNA-binding domain of the AR indicated that the latter is both necessary and sufficient for inhibition of ERA signaling. Consistent with molecular modeling, electrophoretic mobility shift assays showed binding of the AR to an estrogenresponsive element (ERE). Evidence for a functional interaction of the AR with an ERE in vivo was provided by chromatin immunoprecipitation data, revealing recruitment of the AR to the progesterone receptor promoter in T-47D breast cancer cells. We conclude that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17B-estradiol on breast cancer cells. [Cancer Res 2009;69(15):6131-40]