RAC3 is a pro-migratory co-activator of ERα

Estrogen receptor alpha (ER alpha) is a ligand-dependent nuclear receptor that is important in breast cancer genesis, behavior and response to hormone-based therapies. A T7 phage display screen against full-length human ER alpha, coupled with genome-wide exon arrays, was used to identify RAC3 as a putative ER alpha co-regulator. RAC3 is a Rho family small GTPase that is associated with cytoskeletal rearrangement. We demonstrate a novel role for nuclear RAC3 as an ER alpha transcriptional activator, with prognostic implications for metastatic disease. Through in vitro and cell-based studies, RAC3 was shown to exist in a GTP-bound state and act as a ligand specific ER alpha co-activator of E2-induced transcription. Overexpression of RAC3 induced pro-growth and pro-migratory genes that resulted in increased migration of ER alpha-positive breast cancer cells. Chemical inhibition and genetic knockdown of RAC3 antagonized E2-induced cell proliferation, cell migration and ER alpha mediated gene expression, indicating that RAC3 is necessary for full ER alpha transcriptional activity. In agreement with the molecular and cellular data, RAC3 overexpression in ER alpha-positive breast cancers correlated with a significant decrease in recurrence free survival and a significant increase in the odds ratio of metastasis. In conclusion, RAC3 is a novel ER alpha a co-activator that promotes cell migration and has prognostic value for ER alpha-positive breast cancer metastasis. RAC3 may also be a useful therapeutic target for ER alpha-positive breast cancers. Oncogene (2011) 30, 1984-1994; doi:10.1038/onc.2010.583; published online 10 January 2011