Induced Tamoxifen Resistance is Mediated by Increased Methylation of E-Cadherin in Estrogen Receptor-Expressing Breast Cancer Cells

Abstract

Estrogen receptor-positive breast cancers are treated with tamoxifen, a drug that competitively inhibits the binding of estrogen to its receptor. Resistance to tamoxifen is a major hurdle in effective management of target breast cancer patient population. A number of dynamic changes within the tumor microenvironment, including the phenomenon of epithelial to mesenchymal transition (EMT), determine the response to endocrine therapy. EMT is marked by silencing or suppression of epithelial marker, E-Cadherin and we found significantly down-regulated E-Cadherin, among other epithelial markers, and a significantly up-regulated mesenchymal marker, Twist, among other mesenchymal markers, in a model system that comprised of tamoxifen sensitive MCF-7 cells and their tamoxifen-resistant counterparts, MCF-7-TAM, developed by chronic and escalating exposure of parental cells to tamoxifen. Further, E-cadherin, but not Twist, was differentially expressed in MCF-7-TAM cells because of differential methylation. Treatment with demethylating agent 5-azacytidine increased the expression of E-cadherin thus verifying a role of methylation in its silencing and, moreover, 5-azacytidine treatment also re-sensitized MCF-7-TAM cells to tamoxifen, as evaluated by assays for viability, apoptosis and migration potential. The 5-azacytidine effects were similar to effects of E-cadherin overexpression in MCF-7-TAM cells. This work describes novel mechanism of E-cadherin downregulation in tamoxifen resistant breast cancer cells. Further studies are needed to exploit this information for betterment of breast cancer therapy.

Upregulation of PI3K/AKT/PTEN pathway is correlated with glucose and glutamine metabolic dysfunction during tamoxifen resistance development in MCF-7 cells

“…Cells were cultured in two 75-flasks. When the MCF-7 cells were 75–85% confluent, they were treated with gradual doses of Tamoxifen (Santa Cruz Biotechnology, US) starting with a small dose (100 nM) in the first approach and increase the concentrations gradually, as described in the literature 31 , 32 . In the second approach, cells were treated with gradual TAM doses, then fixed doses of 35 µM were given several times 33 .…”

Epigenetic immunomodulatory effect of eugenol and astaxanthin on doxorubicin cytotoxicity in hormonal positive breast Cancer cells

“…Epigenetic modifications were amongst the potential players in hormone resistance. De novo and drug induced alterations in DNA methylation, in the promoter regions of genes, have an impact on the initiation and progression of breast cancer [ 4 , 5 ]. Epigenomic approach through histones acetylation has become a crucial strategy in the way to solve the acquired resistance [ 6 , 7 ].…”

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

“…However, long-term administration of tamoxifen results in an acquired drug resistance in the initially responsive tumor [144]. Resistance may be caused by cells expressing certain regulators interacting with tamoxifen-bound ER [36,37], crosstalk between HER2 and ERα or ligand independent signaling through other pathways of PI3K/mTOR or NFkB [145][146][147], differential microRNA expression [145,[148][149][150][151] or increase in E-cadherin methylation [152], among other mechanisms reviewed elsewhere [153][154][155]. In addition, tamoxifen has an agonistic effect on endometrial cells leading to an increased risk of developing uterine cancer.…”