Estrogen Receptor Alpha Utilizes TRP Channel 6 in Cancer Cell Growth

Abstract

The rapid signaling effects of the hormone estrogen (E2) are mediated through estrogen receptor alpha (ERα) that activates a Ca2+/calmodulin signaling pathway involving CaM KK, CaM KI, and ERK. Additionally, expression of transient receptor potential (TRP) channels, which are Ca2+ channels, may correlate with breast cancer cell growth. In this family of channels, TRPC6 has been shown to be expressed in MCF‐7 breast cancer cells and involved in ERK activation. Since both ERα and TRPC6 increase intracellular calcium levels, ERK activation, and cell growth our goal was to examine if ERα cooperates with TRPC6 to increase CaM Kinase and ERK phosphorylation as well as MCF‐7 cell growth. E2 treatment of MCF‐7 cells led to a significant rise in phosphorylation of CaM KI and its downstream target, ERK, and this effect was blocked by pretreatment with the ERa antagonist MPP. Treatment of MCF‐7 cells with E2 stimulated an increase in MCF‐7 cell growth that was blocked by pretreatment with MPP, but not by pretreatment with the ERb antagonist PHTPP. Interestingly, treatment of cells with the TRP channel inhibitor APB blocked E2 activation of ERK and cell growth. Immunoprecipitation (IP) of endogenous ERa pulled down TRPC6 as did the reciprocal IP from MCF‐7 cells. Confocal microscopy also revealed co‐localization of the proteins in MCF‐7 cells. Our data suggest E2 rapidly activates CaM KI and ERK via ERa and TRP channels and ERa may associate with TRPC6 to regulate breast cancer cell growth.Support or Funding InformationThe Paul K. and Evalyn E. C. Richter Memorial Fund.This work was supported through a Life Science grant from the M.J. Murdock Charitable Trust to J.M.S. grant #2011267.