Abstract
WWOX is a tumor-suppressive steroid dehydrogenase, which relationship with hormone receptors was shown both in animal models and breast cancer patients. Herein, through nAnT-iCAGE high-throughput gene expression profiling, we studied the interplay of estrogen receptors and the WWOX in breast cancer cell lines (MCF7, T47D, MDA-MB-231, BT20) under estrogen stimulation and either introduction of the WWOX gene by retroviral transfection (MDA-MB-231, T47D) or silenced with shRNA (MCF7, BT20). Additionally, we evaluated the consequent biological characteristics by proliferation, apoptosis, invasion, and adhesion assays. TGFα-EGFR signaling was found to be significantly affected in all examined breast cancer cell lines in response to estrogen and strongly associated with the level of WWOX expression, especially in ER-positive MCF7 cells. Under the influence of 17β-estradiol presence, biological characteristics of the cell lines were also delineated. The study revealed modulation of adhesion, invasion, and apoptosis. The obtained results point at a complex role of the WWOX gene in the carcinogenesis of the breast tissue, which seems to be closely related to the presence of estrogen α and/or β receptors.
Highlights
Worldwide, breast cancer (BC) is the most often diagnosed tumor type among women, and is the main causative of death due to oncological disorders (World Cancer Report et al 2014)
T47D and MCF7 breast cancer cell lines were obtained from the American Type Culture Collection (ATCC), and grown according to the manufacturer’s protocol in RPMI-1640 Medium (Gibco) with 2 mM L-glutamine (Gibco), 10 mM HEPES, 1 mM sodium pyruvate, 4500 mg/L glucose, and 1500 mg/L sodium bicarbonate supplemented with 10% heat-inactivated fetal bovine serum (Gibco), antibiotics (Gibco, 0.05 mg/mL penicillin; 0.05 mg/mL streptomycin; 0.1 mg/mL neomycin), and human insulin (ITS insulin/transferrin/selenous acid Premix, BD Biosciences), in a humidified atmosphere containing 5% CO2 at 37 °C
We have assayed ERα (ESR1) and ERβ (ESR2) target genes according to WWOX low and high expression and estradiol treatment in breast cancer cell lines estrogen receptor alpha (ERα)-positive MCF7 which has native high WWOX gene expression in comparison with BT20 ERα-negative and high WWOX and MDA-MB-231 which is ERα-negative with low WWOX expression
Summary
Breast cancer (BC) is the most often diagnosed tumor type among women, and is the main causative of death due to oncological disorders (World Cancer Report et al 2014). Data published in March 2019 by the Global Cancer Observatory (GLOBOCAN) show that there were 2 088 849 cases of breast cancer diagnosed, and 626 679 deaths due to this type of tumor in the year 2018 (Sharma 2021). In 1996, new estrogen-specific receptor was discovered, and was termed ERβ, and already known receptor ERα (Kuiper et al 1996; Mosselman et al 1996). Both have a similar structure, though are encoded by different genes— ESR1 and ESR2—found at different chromosomal locations (chromosome 6 and 14, respectively).
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