Abstract
GPER is a membrane-associated estrogen receptor of the family of G-protein coupled receptors. For breast cancer, the contribution of GPER to promoting the proliferation and migration of both carcinoma cells and cancer-associated fibroblasts (CAFs) in response to estrogen and other agonists has extensively been investigated. Intriguingly, GPER was previously found to be localized to the nucleus in one isolate of breast CAFs. Moreover, this nuclear GPER was shown to bind regulatory sequences of cancer-relevant target genes and to induce their expression. We decided to find out what induces the nuclear localization of GPER, how general this phenomenon is, and what its functional significance is. We discovered that interfering with N-linked glycosylation of GPER, either by mutation of the predicted glycosylation sites or pharmacologically with tunicamycin, drives GPER into the nucleus. Surveying a small set of CAFs from breast cancer biopsies, we found that a relatively common single nucleotide polymorphism, which results in the expression of a GPER variant with the amino acid substitution P16L, is associated with the nuclear localization of GPER. GPER with P16L fails to be glycosylated, presumably because of a conformational effect on the nearby glycosylation sites. GPER P16L is defective for membrane-associated signaling, but instead acts like an estrogen-stimulated transcription factor. In CAFs, it induces the secretion of paracrine factors that promote the migration of carcinoma cells. This raises the possibility that the GPER P16L polymorphism could be a risk factor for breast cancer.
Highlights
Breast cancer is the most frequently diagnosed type of cancer and the leading cause of cancer death among women worldwide [1]
We initially aimed to determine whether changes in the N-linked glycosylation status of GPER could be associated with its nuclear localization in breast cancer-associated fibroblasts (CAFs)
Our present work demonstrates that it is the lack of N-linked glycosylation of GPER, which drives its nuclear localization
Summary
Breast cancer is the most frequently diagnosed type of cancer and the leading cause of cancer death among women worldwide [1]. It is known that estrogens bind to specific nuclear receptors, the estrogen receptors α (ERα) and β, of which ERα generates a potent stimulus for the proliferation of breast epithelial cells and increases the risk of DNA mutation during replication [3]. GPER belongs to a cell surface receptor family, which conventionally mediates transmembrane signaling of membrane-permeable as well as membrane-impermeable ligands, numerous studies demonstrated that GPER is detectable at the plasma membrane, and at intracellular membranes [13,14,15]. Recent studies showed a peculiar GPER localization in the nucleus of breast cancer-associated fibroblasts (CAFs); this nuclear GPER was even found to be recruited in an estrogenstimulated fashion to chromatin at target genes such as c-FOS and CTGF leading to increased expression of these genes [16, 17]
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