Lymphoma and sarcoma cell lines derived from primary tumors arising in a p53 background exhibit prolifera tive arrest and increased prompt delivery apoptosis upon Cre mediated deletion of Sin3A, suggesting Inhibitors,Modulators,Libraries that Sin3A has oncogenic functions. However, another report suggests that Sin3A functions as a tumor suppressor in non small cell lung cancer, as down regulation of Sin3A mRNA occurs in several cases of NSCLC. These few reports with disparate findings highlight a funda mental lack of understanding of the role of Sin3A in growth and cancer. At the molecular level, Sin3A functions as the scaf folding component of the multi protein Sin3 repressor complex that mediates transcriptional repression of sev eral genes. The Sin3 complex was identified in yeast but is conserved in species through mammals.

The characteristic catalytic activity associated with Sin3A is histone deacetylation via Inhibitors,Modulators,Libraries its interactions with HDAC1/2. Additional components of the complex consist of SAP18/30, which stabilize the Sin3A HDAC interac tion, Inhibitors,Modulators,Libraries and RbAp46/48, which anchor the Sin3 complex on nucleosomes. Sin3A does not possess intrin sic DNA binding activity, so it must be targeted via interaction with other DNA bound factors. Interactions for numerous DNA binding factors and Sin3A have been identified, including Mad, p53, MeCP2, NRSF, CTCF, and ERa as examples. Sin3A can Inhibitors,Modulators,Libraries also interact with other enzymatic proteins, including those capable of histone methylation, DNA methylation, chro matin remodeling, and N acetylglucoseamine transferase activity.

In this report, we expand our previous findings and identify the function of Sin3A in gene expression, survi val, and growth of breast cancer cells. Gene expression analysis identified a specific subset of Sin3A responsive genes that were regulated by both HDAC1/2 dependent and independent mechanisms. Importantly, decreased Sin3A expression Inhibitors,Modulators,Libraries led to an increase in apoptosis and increased expression of several apoptotic genes, which translated into attenuation of cell growth of ERa posi tive and not ERa negative breast cancer cells. This study identifies Sin3A as an essential regulator of growth and survival of ERa positive breast cancer cells, which may have important translational implications for breast cancer patients.

Results Sin3A regulates basal expression and estrogen induced responses of specific genes in breast cancer cells Sin3A is a conserved multifunctional repressor protein present in organisms from yeast to mammals that func tions by regulating gene transcription. Our lab previously showed kinase inhibitor Vandetanib that Sin3A regulated the estrogen induced repression of the ERa gene, ESR1, in the MCF7 breast cancer cell line. To identify other genes regu lated by Sin3A, MCF7 cells were transfected with a scrambled negative control or Sin3A siRNA fol lowed by treatment with vehicle ethanol or 10 nM 17 b estradiol.