The G-protein-coupled estrogen receptor, a gene co-expressed with ERα in breast tumors, is regulated by estrogen-ERα signalling in ERα positive breast cancer cells.

GPER is a seven transmembrane G-protein-coupled estrogen receptor that mediates rapid estrogen actions. Large volumes of data have revealed its association with clinicopathological variables in breast tumors, role in epidermal growth factor (EGF)-like effects of estrogen, potential as a therapeutic target or a prognostic marker, and involvement in endocrine resistance in the face of tamoxifen agonism. GPER cross-talks with estrogen receptor alpha (ERα) in cell culture models implicating its role in the physiology of normal or transformed mammary epithelial cells. However, discrepancies in the literature have obfuscated the nature of their relationship, its significance, and the underlying mechanism. The purpose of this study was to assess the relationship between GPER, and ERα in breast tumors, to understand the mechanistic basis, and to gauge its clinical significance. We mined The Cancer Genome Atlas (TCGA)-BRCA data to examine the relationship between GPER and ERα expression. GPER mRNA, and protein expression were analyzed in ERα-positive or -negative breast tumors from two independent cohorts using immunohistochemistry, western blotting, or RT-qPCR. The Kaplan-Meier Plotter (KM) was employed for survival analysis. The influence of estrogen in vivo was studied by examining GPER expression levels in estrus or diestrus mouse mammary tissues, and the impact of 17ß-estradiol (E2) administration in juvenile or adult mice. The effect of E2, or propylpyrazoletriol (PPT, an ERα agonist) stimulation on GPER expression was studied in MCF-7 and T47D cells, with or without tamoxifen or ERα knockdown. ERα-binding to the GPER locus was explored by analysing ChIP-seq data (ERP000380), in silico prediction of estrogen response elements, and chromatin immunoprecipitation (ChIP) assay. Clinical data revealed significant positive association between GPER and ERα expression in breast tumors. The median GPER expression in ERα-positive tumors was significantly higher than ERα-negative tumors. High GPER expression was significantly associated with longer overall survival (OS) of patients with ERα-positive tumors. In vivo experiments showed a positive effect of E2 on GPER expression. E2 induced GPER expression in MCF-7 and T47D cells; an effect mimicked by PPT. Tamoxifen or ERα-knockdown blocked the induction of GPER. Estrogen-mediated induction was associated with increased ERα occupancy in the upstream region of GPER. Furthermore, treatment with 17ß-estradiol or PPT significantly reduced the IC50 of the GPER agonist (G1)-mediated loss of MCF-7 or T47D cell viability. In conclusion, GPER is positively associated with ERα in breast tumors, and induced by estrogen-ERα signalling axis. Estrogen-mediated induction of GPER makes the cells more responsive to GPER ligands. More in-depth studies are warranted to establish the significance of GPER-ERα co-expression, and their interplay in breast tumor development, progression, and treatment.

Concurrent Chemoradiation for Cancer of the Cervix: Results of a Multi-Institutional Study From the Setting of a Developing Country (India).

PURPOSE: The primary output of hospital-based cancer registries is data on cancer stage and treatment-based survival that can be used to evaluate patient care, but because there are many challenges in obtaining follow-up details, a separate study on patterns of care and patterns of survival for patients at selected sites was initiated under the National Cancer Registry Programme of India. This article presents the results for cervical cancer. PATIENTS AND METHODS: A standardized patient information form was used to record patient information, and data were entered into a central repository-the National Centre for Disease Informatics and Research. The study patients were from 12 institutions and were diagnosed between January 1, 2006, and December 31, 2008. Patterns of treatment were assessed for 7,336 patients, and patterns of survival were determined for 2,669 patients from six institutions, at least 70% of whom had data regarding follow-up as of December 31, 2012. RESULTS: Of 7,336 patients, 55.5% received optimal radiotherapy (RT). In all, 80.9% of patients had locally advanced cancers (stage IIB to IVA), 51.1% received RT alone, and 44.4% received concurrent chemoradiation (RTCT). In 1,753 patients with locally advanced cancers, significantly better survival was observed with RTCT than with RT alone (5-year cumulative survival, 70.2% v 47.3%; hazard ratio, 0.48; 95% CI, 0.41 to 0.56). CONCLUSION: A conservative estimate indicates that, on an annual basis, 38,771 patients with cervical cancers in India alone do not get the benefit of RTCT and thus they have poorer survival. There is a need to reiterate the National Cancer Institute's alert that advised supplementing chemotherapy to radiation for locally advanced cancer of the cervix in the context of the developing world, where 84.3% of cancers of the cervix occur.

Association of interleukin-1ß -511 C/T polymorphism with tobacco-associated cancer in northeast India: a study on oral and gastric cancer.

The IL-1ß -511 C/T polymorphism is associated with increased IL-1 production and with increased risk of developing cancers. In this study, 251 patients (125 with gastric cancer [GC] and 126 with oral cancer [OC]) and 207 normal controls from northeast (NE) India were genotyped for the IL-1ß -511 C/T polymorphism by PCR-restriction fragment length polymorphism (RFLP) and sequencing. Analysis of results showed betel-quid chewing to be a major risk factor (OR = 2.01, 95% CI = 1.05-3.87; P = 0.035) for OC. Inheritance of the IL-1ß -511 CT or TT resulted in a 2.6- to 3.05-fold increase in the risk of developing OC relative to that of participants who possessed the reference genotype (OR = 2.57, 95% CI = 1.06-6.22; P = 0.036 and OR = 3.05, 95% CI = 1.22-7.63; P = 0.017), after adjusting for potential confounders. The dominant genetic model also confirmed the presence of the T allele as a significant risk factor for OC (OR = 2.72, 95% CI = 1.15-6.42; P = 0.02). In GC, interaction of the CT genotype with tobacco and betel-quid chewing habits conferred a significant 78% and 89% reduced risk of cancer, respectively. In conclusion, for the NE Indian population, the IL-1ß -511 CC and CT genotypes were significantly associated with increased risk of OC. However, the interaction of the CT genotype with risk habits may play a preventive role for GC but not for OC.