Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen-Responsive Cancer Cells via Activating Mutations

Figure 1

Regulatory circuits driven by liganded ER-alpha for DNA stabilization (A), cell proliferation (B), and fuel supply (C). Circuit A: Estrogen- (E₂) activated estrogen receptor alpha (ERα) upregulates estrogen signaling via a regulatory circuit together with genome stabilizer protein (BRCA1) and aromatase enzyme (A450). Activated ER-alpha induces messenger RNA (mRNA) expressions on ESR1, BRCA1, and Cyp19A aromatase promoter regions upregulating the synthesis of ER-alpha, BRCA1, and aromatase enzyme. Aromatase enzyme produces estrogen hormones for further ER activation. In addition, activated ER-alpha may induce activating mutations on ESR1, BRCA1, and Cyp19A genes through the expression and activation of appropriate long noncoding RNAs (lncRNAs). In addition, ER-alpha and BRCA proteins are capable of direct binding as transcriptional factors regulating each other’s activity. Circuit B: Estrogen activated ERα is the crucial regulator of increased and decreased cell proliferation in strong interplay with membrane-associated tyrosine kinase growth factor receptors, EGFRs and IGF-1Rs. ERs regulate the expression and activation of growth factors (GFs) and their receptors. Transduction of growth factor signaling (GFS) induces kinase cascades via PI3-K/AKT/mTOR and RAS/RAF/MEK/MAPK pathways, which are transmitted into the nucleus inducing expressions of specific genes through an unliganded activation of ERs. Circuit C: Estrogen activated ERα is the regulator of all steps of cellular glucose uptake and the maintenance of glucose homeostasis. Estrogen-regulated genes stimulate both insulin synthesis and insulin receptor (IR) expression. Activated ERα stimulates the expression and activation of GLUT4 facilitating cellular glucose uptake. In addition, estrogen-activated ERα at the plasma membrane stimulates the kinase cascade of the PI3-K/AKT/mTOR pathway via IRS-1 activation. These signals induce specific gene expressions in the nucleus conferred by unliganded ERα activation. CA: coactivator, AF2: ligand binding domain, and AF1: nonligand binding domain.