Exploring the Tumor Suppressive Roles of Estrogen Receptor β in Lung and Breast Cancer



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Estrogens represent a subclass of steroid hormones that by regulating cell growth and differentiation, influence normal physiology as well as pathology. The effects of estrogen are mediated by two members of the nuclear receptor superfamily, Estrogen Receptor α (ERα) and ERβ. A plethora of studies have shown that ERα and ERβ exert opposite effects on cancer development and progression by eliciting distinct transcriptional responses and differentially influencing cellular processes such as cell proliferation, apoptosis, and migration. The present study focused on the potential role of ERβ in affecting development and progression of the two most commonly diagnosed cancers in men and women, lung and breast cancer, respectively. Our studies revealed that upregulation of wild-type ERβ (ERβ1), but not the splice variant ERβ2, reduces proliferation and enhances apoptosis in non-small cell lung cancer (NSCLC) cells. ERβ1 was found to induce apoptosis by stimulating the intrinsic apoptotic pathway that involved upregulation of the pro-apoptotic factor BIM and downregulation of components of the growth factor signaling pathway. Manipulation of EGFR and RAS expression and activity in ERβ1-expressing cells revealed the central role of oncogenic RAS signaling in ERβ1-mediated pro-apoptotic phenotype and EGFR regulation. In addition, our studies demonstrated that ERβ1 sensitizes NSCLC cells to chemotherapeutic agents. Upregulation of ERβ1 decreased the viability of doxorubicin- and etoposide-treated NSCLC cells by inducing G2/M phase cell cycle arrest. In response to treatment, ERβ1-expressing cells had increased p-Chk1 levels, an indicator of activated DNA damage response, compared with the control cells. Finally, we showed that ERβ1 represses epithelial to mesenchymal transition (EMT) and invasion of basal-like breast cancer cells both in vitro and in vivo. ERβ1 impeded EMT by downregulating EGFR. EGFR downregulation in ERβ1-expressing cells was associated with the stabilization of the ubiquitin ligase c-Cbl-EGFR complexes that led to increased ubiquitylation and degradation of the activated receptor. In conclusion, our studies have unveiled the important role of ERβ in regulating crucial processes of lung and breast cancer development and progression and propose ERβ as a potential biomarker for predicting metastasis in breast cancer and response to treatment in NSCLC.



Estrogen receptor beta, EGFR, NSCLC, RAS, DNA damage response, P53, EMT, Basal-like, E-cadherin


Portions of this document appear in: Nikolos F, Thomas C, Rajapaksa G, Bado I, Gustafsson JA. ERbeta regulates NSCLC phenotypes by controlling oncogenic RAS signaling. Molecular cancer research : MCR. 2014;12:843-54. And in: Thomas C, Rajapaksa G, Nikolos F, Hao R, Katchy A, McCollum CW, et al. ERbeta1 represses basal breast cancer epithelial to mesenchymal transition by destabilizing EGFR. Breast cancer research : BCR. 2012;14:R148.