Selective hormone-dependent repression of estrogen receptor beta by a p38-activated ErbB2/ErbB3 pathway

Deregulated signaling of ErbB2 receptor tyrosine kinase is often associated with hormone resistance in estrogen receptor alpha (ERα)-positive breast cancers, establishing a relationship between ErbB2 and ERα pathways. Although ERα and ERβ are expressed in many breast cancer cells, the response of ERβ to ErbB2 signaling is less well defined. In the present study, we demonstrate that ERβ activity can be modulated by ErbB2 signaling in ER-expressing breast cancer cells. The estrogen-dependent transcriptional activity of ERβ was altered in a manner similar to ERα by either activation of ErbB2/ErbB3 signaling by growth factor heregulin β or expression of a constitutively active mutant of ErbB2. However, as opposed to ERα, the p38 MAPK pathway was found to be involved in liganded ERβ repression activity by ErbB2 signaling and in regulating estrogen-responsive promoter occupancy by ERβ. The repression in ERβ response to hormone was dependent upon its AF-1 domain which includes serines 106 and 124, two phosphorylation target sites for Erk that we previously showed to be involved in SRC-1 recruitment to ERβ. Substitution of these two serines by aspartic acid residues abolished the repression of ERβ by activated ErbB2/ErbB3. Moreover, expression of SRC-1 also relieved the inhibition of ERβ in heregulin-treated cells. Our study demonstrates a functional coupling between ERβ and ErbB receptors and outlines the differential role of the AF-1 region in the regulation of the estrogen-dependent cell growth and activity of both estrogen receptors in response to growth factor signaling.