RhoB modifies estrogen responses in breast cancer cells by influencing expression of the estrogen receptor.

Abstract : ABSTRACT: INTRODUCTION: RhoB has been reported to exert positive and negative effects on cancer pathophysiology but an understanding of its role in breast cancer remains incomplete. Analysis of data from the Oncomine database showed a positive correlation between RhoB expression and positivity for both the Estrogen Receptor alpha (ERalpha) and the Progesterone Receptor (PR). METHODS: This finding was validated by our analysis of a tissue microarray constructed from a cohort of 113 patients and then investigated in human cell models. RESULTS: We found that RhoB expression in tissue was strongly correlated with ER and PR expression and inversely correlated with tumor grade, tumor size and count of mitosis. In human breast cancer cell lines, RhoB attenuation was associated with reduced expression of both ERalpha and PR, whereas elevation of RhoB was found to be associated with ERalpha overexpression. Mechanistic investigations suggested that RhoB modulates ERalpha expression controlling both its protein and mRNA levels, and that RhoB modulates PR expression by accentuating the recruitment of ERalpha and other major co-regulators to the promoter of PR gene. A major consequence of RhoB modulation was that RhoB differentially regulated the proliferation of breast cancer cell lines. Interestingly, we documented crosstalk between RhoB and ERalpha, with estrogen treatment leading to RhoB activation. CONCLUSIONS: Taken together, our findings offer evidence that in human breast cancer RhoB acts as a positive function to promote expression of ERalpha and PR in a manner correlated with cell proliferation.