Journal article
A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis
The Journal of steroid biochemistry and molecular biology, Vol.176, pp.38-48
02/2018
DOI: 10.1016/j.jsbmb.2017.05.005
PMID: 28595943
Abstract
•Estrogen exposure and obesity are risk factors for female reproductive cancers.•GPER is linked to obesity, vascular pathology and immunosuppression, and directly associated with tumor progression variables in breast, ovarian, and endometrial cancer.•GPER is associated with cell survival signaling pathways that are associated with extracellular matrix synthesis, growth factor responsiveness and cell cycle progression.•GPER activates cellular activities necessary for epithelial-mesenchymal transition (EMT) and survival outside of the context of reproductive glandular epithelia.
Mechanisms of carcinogenesis by estrogen center on its mitogenic and genotoxic potential on tumor target cells. These models suggest that estrogen receptor (ER) signaling promotes expansion of the transformed population and that subsequent accumulation of somatic mutations that drive cancer progression occur via metabolic activation of cathecol estrogens or by epigenetic mechanisms. Recent findings that GPER is linked to obesity, vascular pathology and immunosuppression, key events in the development of metabolic syndrome and intra-tissular estrogen synthesis, provides an alternate view of estrogen-induced carcinogenesis. Consistent with this concept, GPER is directly associated with clinicopathological indices that predict cancer progression and poor survival in breast and gynecological cancers. Moreover, GPER manifests cell biological responses and a microenvironment conducive for tumor development and cancer progression, regulating cellular responses associated with glandular homeostasis and survival, invading surrounding tissue and attracting a vascular supply. Thus, the cellular actions attributed to GPER fit well with the known molecular mechanisms of G-protein coupled receptors, GPCRs, namely, their ability to transactivate integrins and EGF receptors and alter the interaction between glandular epithelia and their extracellular environment, affecting epithelial-to-mesenchymal transition (EMT) and allowing for tumor cell survival and dissemination. This perspective reviews the molecular and cellular responses manifested by GPER and evaluates its contribution to female reproductive cancers as diseases that progress as a result of dysregulated glandular homeostasis resulting in chronic inflammation and metastasis.
This review is organized in sections as follows: I) a brief synopsis of the current state of knowledge regarding estrogen-induced carcinogenesis, II) a review of evidence from clinical and animal-based studies that support a role for GPER in cancer progression, and III) a mechanistic framework describing how GPER-mediated estrogen action may influence the tumor and its microenvironment.
Details
- Title: Subtitle
- A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis
- Creators
- Edward J Filardo - Division of Hematology & Oncology, The Warren Alpert School of Medicine, Brown University, Providence, RI 02818, United States
- Resource Type
- Journal article
- Publication Details
- The Journal of steroid biochemistry and molecular biology, Vol.176, pp.38-48
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/j.jsbmb.2017.05.005
- PMID
- 28595943
- ISSN
- 0960-0760
- eISSN
- 1879-1220
- Language
- English
- Date published
- 02/2018
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Surgery; Internal Medicine
- Record Identifier
- 9984051720602771
Metrics
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