Catechol estrogen quinones as initiators of breast and other human cancers: Implications for biomarkers of susceptibility and cancer prevention ☆

Select changes in microRNA (miRNA) expression correlate with estrogen receptor α (ERα) expression in breast tumors. miR-21 is higher in ERα positive than negative tumors, but no one has examined how estradiol (E2) regulates miR-21 in breast cancer cells. Here we report that E2 inhibits miR-21 expression in MCF-7 human breast cancer cells. The E2-induced reduction in miR-21 was inhibited by 4-hydroxytamoxifen (4-OHT), ICI 182 780 (Faslodex), and siRNA ERα indicating that the suppression is ERα-mediated. ERα and ERβ agonists PPT and DPN inhibited and 4-OHT increased miR-21 expression. E2 increased luciferase activity from reporters containing the miR-21 recognition elements from the 3′-UTRs of miR-21 target genes, corroborating that E2 represses miR-21 expression resulting in a loss of target gene suppression. The E2-mediated decrease in miR-21 correlated with increased protein expression of endogenous miR-21-targets Pdcd4, PTEN and Bcl-2. siRNA knockdown of ERα blocked the E2-induced increase in Pdcd4, PTEN and Bcl-2. Transfection of MCF-7 cells with antisense (AS) to miR-21 mimicked the E2-induced increase in Pdcd4, PTEN and Bcl-2. These results are the first to demonstrate that E2 represses the expression of an oncogenic miRNA, miR-21, by activating estrogen receptor in MCF-7 cells.

Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells.

There is a clear association between the excessive exposure to estrogens and the development of cancer in hormone-sensitive tissues (breast, endometrium). It has become clear that there are likely multiple overlapping mechanisms of estrogen carcinogenesis. One major pathway is the extensively studied hormonal pathway, by which estrogen stimulates cell proliferation through nuclear estrogen receptor (ER)-mediated signaling, thus resulting in an increased risk of genomic mutations during DNA replication. A similar “nongenomic pathway”, potentially involving newly discovered membrane-associated ERs, also appears to regulate extranuclear estrogen signaling pathways. This perspective is focused on a third pathway involving the metabolism of estrogens to catechols mediated by cytochrome P450 and further oxidation of these catechols to estrogen o-quinones. Oxidative enzymes, metal ions, and in some cases molecular oxygen can catalyze o-quinone formation, so that these electrophilic/redox-active quinones can caus...

Potential mechanisms of estrogen quinone carcinogenesis.

Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis

The past decade has seen marked fluctuations in opinions concerning the merits and risks of postmenopausal hormone therapy. In July 2002, menopause management faced a major turning point when the f...

IMS updated recommendations on postmenopausal hormone therapy.

Breast cancer is a malignancy whose dependence on estrogen exposure has long been recognized even though the mechanisms whereby estrogens cause cancer are not clearly understood. This work was performed to determine whether 17beta-estradiol (E2), the predominant circulating ovarian steroid, is carcinogenic in human breast epithelial cells and whether nonreceptor mechanisms are involved in the initiation of breast cancer. For this purpose, the effect of four 24 h alternate periods of 70 nM E2 treatment of the estrogen receptor alpha (ER-alpha) negative MCF-10F cell line on the in vitro expression of neoplastic transformation was evaluated. E2 treatment induced the expression of anchorage-independent growth, loss of ductulogenesis in collagen, invasiveness in Matrigel, and loss of 9p11-13. Only invasive cells that exhibited a 4p15.3-16 deletion were tumorigenic. Tumors were poorly differentiated ER-alpha and progesterone receptor-negative adenocarcinomas that expressed keratins, EMA, and E-cadherin. Tumors and tumor-derived cell lines exhibited loss of chromosome 4, deletions in chromosomes 3p12.3-13, 8p11.1-21, 9p21-qter, and 18q, and gains in 1p, and 5q15-qter. The induction of complete transformation of MCF-10F cells in vitro confirms the carcinogenicity of E2, supporting the concept that this hormone could act as an initiator of breast cancer in women. This model provides a unique system for understanding the genomic changes that intervene for leading normal cells to tumorigenesis and for testing the functional role of specific genomic events taking place during neoplastic transformation.

17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells

Prolonged unopposed estrogen exposure is a widely accepted risk factor in breast cancer development. However, the mechanisms through which estrogens induce breast carcinogenesis have not been definitively unraveled. For testing whether estrogens exert their transforming effects through a non-receptor-mediated mechanism, we have treated the spontaneously immortalized human breast epithelial cells MCF-10F, which are estrogen receptor alpha negative, with 17-beta estradiol (E(2)) or its metabolite 4-OH-estradiol (4-OH-E(2)), each one either alone or in combination with the antiestrogen ICI-182-780. Treated cells were maintained for several passages in culture and evaluated for colony formation in agar-methocel (CE), tri-dimensional growth in collagen matrix, invasiveness in matrigel, and cell cycle analysis by flow cytometry. Both E(2) and 4-HO-E(2), at all the doses tested, in the presence or absence of ICI-182-780, increased CE and decreased the cells' ductulogenic capacity. They also increased the invasiveness and the number of cells in the S phase of the cell cycle. Our data clearly demonstrate that E(2) and 4-OH-E(2) increase cell proliferation and induce transformation in MCF-10F cells, phenomena that are not abrogated by ICI-182-780. The failure of the antiestrogen to abrogate the transformation phenotypes led us to hypothesize that estrogen-induced transformation is occurring by a non-estrogen receptor alpha-mediated process, more probably through the genotoxic effect of the estrogen metabolite 4-HO-E(2).

The estrogen antagonist ICI-182-780 does not inhibit the transformation phenotypes induced by 17-beta-estradiol and 4-OH estradiol in human breast epithelial cells.

http://www.annalsofoncology.org/article/S0923753422003866/pdf

VP1-2022: Pre-specified event driven analysis of Overall Survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer

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17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells

The estrogen antagonist ICI-182-780 does not inhibit the transformation phenotypes induced by 17-beta-estradiol and 4-OH estradiol in human breast epithelial cells.

VP1-2022: Pre-specified event driven analysis of Overall Survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer