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Review
. 2020 Jul 28:2020:5418365.
doi: 10.1155/2020/5418365. eCollection 2020.

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

Affiliations
Review

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

Zsuzsanna Suba. J Oncol. .

Abstract

Cancer cells are embarrassed human cells exhibiting the remnants of same mechanisms for DNA stabilization like patients have in their healthy cells. Antiestrogens target the liganded activation of ERs, which is the principal means of genomic regulation in both patients and their tumors. The artificial blockade of liganded ER activation is an emergency situation promoting strong compensatory actions even in cancer cells. When tumor cells are capable of an appropriate upregulation of ER signaling resulting in DNA repair, a tumor response may be detected. In contrast, when ER signaling is completely inhibited, tumor cells show unrestrained proliferation, and tumor growth may be observed. The laboratory investigations of genomic mechanisms in antiestrogen-responsive and antiestrogen-unresponsive tumor cells have considerably enhanced our knowledge regarding the principal regulatory capacity of estrogen signaling. In antiestrogen-responsive tumor cells, a compensatory increased expression and liganded activation of estrogen receptors (ERs) result in an apoptotic death. Conversely, in antiestrogen resistant tumors exhibiting a complete blockade of liganded ER activation, a compensatory effort for unliganded ER activation is characteristic, conferred by the increased expression and activity of growth factor receptors. However, even extreme unliganded ER activation is incapable of DNA restoration when the liganded ER activation is completely blocked. Researchers mistakenly suspect even today that in tumors growing under antiestrogen treatment, the increased unliganded activation of estrogen receptor via activating mutations is an aggressive survival technique, whilst it is a compensatory effort against the blockade of liganded ER activation. The capacity of liganded ERs for genome modification in emergency states provides possibilities for estrogen/ER use in medical practice including cancer cure.

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Conflict of interest statement

The author declares that there are no conflicts of interest.

Figures

Figure 1
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.
Figure 2
Figure 2
Emergency response to tamoxifen (T) treatment in tumor cells. The rapid translocation of unbound estrogen receptors (ERs) out of the nucleus facilitates their interactions with membrane-associated growth factor receptors (IGF1-R and EGFR) inducing their unliganded activation. Activated cytoplasmic ERs initiate rapid transcriptional processes in the nucleus through transcriptional factors (TFs). Growth factor- (GF-) activated GFRs may also induce unliganded activation on nuclear unbound ERs driving their transcriptional activity. E: estrogen; P: phosphorylation; N: nucleus; red arrow: activation; black arrow: inhibition.
Figure 3
Figure 3
Mechanism of tumor response in cancer cells treated with tamoxifen (T). Abundant unliganded estrogen receptor (ER) activation increases the expression of estrogen-regulated genes upregulating the circuit of ER-aromatase-E2-ER expression. In the meantime, growth factors (GFs) activate growth factor receptors (GFRs) activating free nuclear ERs via an unliganded pathway. The predominance of estrogen- (E-) bound ERs over T-bound ones leads to DNA repair, apoptotic death, and clinical tumor response. P: phosphorylation; N: nucleus; red arrow: activation; black arrow inhibition.
Figure 4
Figure 4
Mechanism of tumor resistance in cancer cells treated with tamoxifen (T). The liganded activation of abundant estrogen receptors (ERs) is completely blocked by T binding, and they are deregulated instead of activation. Compensatory abundant expression of growth factor receptors (GFRs) struggles for the unliganded activation of T-bound ERs, while the T blockade of the liganded pathway inhibits the restoration of ER signaling. GF: growth factor; N: nucleus; red arrow: activation; black arrow: inhibition.

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