The mechanism by which estrogen treatment increases Sin3A sellckchem protein levels is likely via a secondary effect since elevated levels are not seen before 24 hours. Differ ent ERa positive cell types also seem to have a greater dependency on Sin3A levels for survival and growth than others. For example, we find a greater induction of Sin3A protein in MCF7 than T47D cells, and subsequently, a greater effect of Sin3A on growth of MCF7 cells. While this manuscript was under revision, another group published that the Sin3 complex represses the ERa gene, ESR1, in ERa negative breast cancer cell lines. Consistent with this finding, Inhibitors,Modulators,Libraries we showed Sin3A regulation of estrogen induced repression of ESR1 in MCF7 cells. However, unlike the other publication, we did not observe reexpression of either ESR1 mRNA or ERa protein in MDA MB 231 in our current studies.

These dis crepancies may be due to different experimental condi tions and techniques. Importantly, the authors in disrupted Sin3A and Sin3B function by using the Sin3 interaction domain of the MAD protein, while our experiments focused only on Sin3A. Additionally, the SID from MAD may participate in other protein interactions beyond the Sin3 proteins. Together, Inhibitors,Modulators,Libraries these reports suggest that components besides Sin3A are necessary to mediate the repression of ESR1 in ERa negative cells. Finally, our data show several converging Inhibitors,Modulators,Libraries points between Sin3A and the estrogen signaling pathway. As described above, estrogen increases protein levels of Sin3A, suggesting a feedback loop to control estrogen dependent growth.

Our previous report shows Inhibitors,Modulators,Libraries that Sin3A controls expression of the ERa gene itself, ESR1, and Sin3A can interact with ERa in ERa positive breast cancer cells. We further show here that Sin3A con trols expression of NCOA2, a member of the p160 coac tivator family involved in mediating ERa transcriptional activation. The estrogen induced acti vation of PGR, which encodes the progesterone receptor, also increases upon Sin3A knockdown. PR status is often used as a marker of estrogen sen sitivity and predictor of response to endocrine therapy in breast cancer. Additionally, knockdown of Sin3A only prevents growth of ERa positive Inhibitors,Modulators,Libraries MCF7 and T47D cells, not ERa negative MDA MB 231 and Hs578T cells, further supporting the notion that compo nents intrinsic to the ERa signaling pathway are involved in mediating the ability of Sin3A to check details promote survival. Conclusions This is one of the first studies to analyze the role of the Sin3A transcriptional repressor protein in breast cancer. We find that Sin3A regulates the expression of several genes important in breast cancer and estrogen signaling, and these effects are mediated through both HDAC1/2 dependent and independent mechanisms of Sin3A.