Impact of estrogen receptor β on gene networks regulated by estrogen receptor α in breast cancer cells

Two subtypes of the estrogen receptor (ER), ER alpha and ER beta, mediate the actions of estrogens, and although 70% of human breast cancers express ER beta along with ER alpha, little is known about the possible comodulatory effects of these two ERs. To investigate this, we have used adenoviral gene delivery to produce human breast cancer (MCF-7) cells expressing different levels of ER beta, along with their endogenous ER alpha, and have examined the effects of ER beta and receptor occupancy, using ER subtype selective ligands, on genome-wide gene expression by microarray and pathway network analysis. ER beta had diverse effects on gene expression, enhancing or counteracting ER alpha regulation for distinct subsets of estrogen target genes. Strikingly, ER beta in the absence of estradiol (E2), elicited the stimulation or suppression of many genes that were normally only regulated by ER alpha with E2. In addition, ER beta plus E2 elicited the expression of a unique group of genes that were not regulated by ER alpha plus E2 alone. The expression of genes in many functional categories were modulated by ER beta, with the greatest numbers associated with transcription factors and signal transduction pathways. Regulation of multiple components in the TGF beta and semaphorin pathways, and of genes controlling cell cycle progression and apoptosis, may contribute to the suppression of cell proliferation observed with ER beta. Our observations suggest that the relative levels of ER beta and ER alpha in breast cancers are likely to impact cell proliferation and the activities of diverse signaling pathways and their response to ER ligands and endocrine therapies.