Cohesin proteins are essential for chromosome segregation, DNA damage repair and tissue specific gene regulation. Altered expression and/or mutations in cohesins are linked to a variety of cancers, including breast cancer. Intriguingly, amplification of cohesin subunit RAD21 in luminal breast cancersis correlated with poor prognosis1 and development of resistance to endocrine therapy. However, the correlation between elevated levels of RAD21 and prognostic/therapeutic outcomes in breast cancer is not understood fully.
Cohesin co-localizes with estrogen receptor α (ERα) at multiple genomic sites in breast cancer cells2, implying that it could modulate estrogen-regulated transcription. Our lab discovered that the proto-oncogene MYC is dependent on cohesin for its activation by estrogen3 and is also positively regulated by cohesin4. These data led to our hypothesis that a cohesin-estrogen pathway might contribute to the etiology of this subtype of breast cancer.
To test this hypothesis, we sought to identify how estrogen-responsive gene expression alters upon depletion of cohesin. We conducted a microarray expression analysis in cohesin-depleted MCF-7 cells in the presence/absence of estrogen. Affected molecular networks include the ErbB and mTOR signaling pathways. In-silico binding analysis revealed that most significantly dysregulated genes are co-bound by ERα and cohesin, suggesting potential for their direct regulation by cohesin.
To determine if blocking cohesin’s function would prevent expression of cohesin-ERα target genes, we are investigating the action of PCI-34051, an inhibitor of HDAC8, which is a deacetylase for cohesin subunit SMC3. Our preliminary data shows that PCI-34051 inhibits MCF-7 cell-proliferation in a dose-dependent manner and leads to the accumulation of acetylated-SMC3. We hope that this research will improve our understanding of breast cancer pathology and open avenues for the development of novel combination therapies.