![Sample our Medicine, Dentistry, Nursing & Allied Health journals, sign in here to start your FREE access for 14 days]({"type":"image" , "src" : "/sda/5944/TOC-Subject-Sample-2021-Medicine-Dentistry-Nursing-Allied-Health.jpg"})
ABSTRACT
Introduction: Breast cancer is clinically classified as ‘estrogen-positive’ when at least 1% of cancer cells stain for the estrogen receptor alpha (ERα). However, recent research on both basic and clinical aspects of breast cancer suggests that GPER-1 (G protein-coupled estrogen receptor-1) may have an important role in breast cancer.
Areas covered: This review provides a comprehensive and systematic literature search on GPER-1. We have focused on the role of GPER-1 in breast cancer and on resistance to endocrine therapy, an unsolved clinical issue still under discussion.
Expert opinion: The discovery of GPER-1 as a novel estrogen receptor is unique and the signaling pathways activated by its stimulation, when compared to the classical nuclear ERα, indicate a potential role of GPER-1 in the genesis and mechanisms of drug resistance in breast cancer. Tumors expressing ERα represent the largest group of breast cancer patients indicating that more women eventually die from ERα-positive breast tumors than from other more malignant breast cancer subtypes such as HER2-positive and the triple negative groups. It is important to develop new strategies on endocrine therapy with regard to ERα and GPER-1 receptors to achieve innovative successful therapeutic tools.
Article highlights
Of the classical estrogen receptors, named as alpha (ERα) and beta (ERβ), ERα is the most investigated and targeted by ERα antagonists such as tamoxifen or the use of aromatase inhibitors.
GPER-1, considered an orphan receptor until 2005, is a novel estrogen receptor coupled to G proteins that like other G protein-coupled receptors is localized on the cell membrane.
In humans, the GPER-1 gene is located on 7p22.3 chromosome and encodes a protein that contains 375 amino acids with a theoretical molecular mass of 41 kDa.
In contrast to ERα66 knockout mice, GPER-1 null mice show no reproductive deficits, and the response of the mammary gland to estrogen is similar to that observed in wild-type animals. Nevertheless, GPER-1 null mice clearly show absence of numerous estrogen-mediated effects.
GPER-1 is highly expressed in a variety of tissues including the breast and in estrogen-dependent diseases such as breast cancer, most of which depend on activation of estrogen receptors to grow and disseminate.
The membrane localization of ERα is controversial. However, the variant ERα36 has been shown to localize in plasma membrane of both breast cancer cell lines as well as tumor tissue from breast cancer patients.
Stimulation of GPER-1 results in activation of signaling pathways involved in cell proliferation, survival and invasion, events that may be amplified by transactivation of epidermal growth factor receptor (EGFR).
Tamoxifen and fulvestrant display an agonistic effect on GPER-1, an attribute that must be considered when breast cancer patients are undergoing endocrine therapy because GPER-1 may be responsible for tumor resistance.
This box summarizes key points contained in the article.
Acknowledgments
The authors wish to thank Mr. Cristian Herrera who helped us with confocal images for GPER-1 immunolabeling and Dr. Maite Poblete for her valuable comments.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.