High FGFR2 expression is associated with reduced breast cancer risk and represses the estrogen response
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE74663 | GEO | 2015/11/04
SECONDARY ACCESSION(S): PRJNA301107
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-11-04 | E-GEOD-74663 | biostudies-arrayexpress
Project description:High FGFR2 expression is associated with reduced breast cancer risk and represses the estrogen response
| PRJNA301107 | ENA
Project description:Estrogen receptor ? (ER?) mediates the effects of 17?-estradiol (E2) in normal mammary gland, and it is a key participant in breast cancer tumor development. ER? transactivation activity is mediated by the synergistic interaction of two domains designated AF1 and AF2. The function of AF2 is to recruit coactivator and corepressor proteins that allow ER? to oscillate between the roles of transcriptional activator and repressor. In contrast, the mechanism responsible for AF-1 transcriptional activity is not completely understood. In this study, we identified tristetraproline (TTP) as a novel ER?-associated protein. TTP expression in MCF7 cells repressed ER? transactivation and reduced MCF7 cell proliferation and the ability of the cells to form tumors in a mouse model. We show that TTP transcriptional activity is mediated through its recruitment to the promoter region of ER? target genes and its interaction with histone deacetylases, in particular with HDAC1. TTP expression attenuates the coactivating activity of SRC-1, suggesting that exchange between TTP and other coactivators may play an important role in fine-tuning ER? transactivation. These results indicate that TTP acts as a bona fide ER? corepressor and suggest that this protein may be a contributing factor in the development of E2-dependent tumors in breast cancer.
| S-EPMC4140911 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-07-17 | E-GEOD-48931 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2013-07-17 | GSE48931 | GEO
Project description:Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression and activity in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance, basal-like differentiation, and invasion. A functional drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-α signaling. Among these, the Transforming Growth Factor-β and the Janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced modulation of ER-α activity. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-α expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.
| S-EPMC10997519 | biostudies-literature
Project description:AIMS AND BACKGROUND:Breast cancer is one of the most common neoplasms among women in many developing countries including China, and is the leading cause of female cancer-related deaths worldwide. METHODS:In the current study, we analyzed the relationship between 14 tag single-nucleotide polymorphisms (tSNPs) and breast cancer risk in the Han Chinese population including 185 breast cancer patients and 199 healthy women controls on the different types of breast cancer and menopausal status. RESULTS:Overall, we found rs2981579 in the FGFR2 gene, and rs2380205 were associated with breast cancer susceptibility. CONCLUSIONS:These findings indicate that FGFR2 was associated with breast cancer risk in the Han Chinese population, support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations.
| S-EPMC4497451 | biostudies-literature
Project description:The fibroblast growth factor receptor 2 (FGFR2) locus has been consistently identified as a breast cancer risk locus in independent genome-wide association studies. However, the molecular mechanisms underlying FGFR2-mediated risk are still unknown. Using model systems we show that FGFR2-regulated genes are preferentially linked to breast cancer risk loci in expression quantitative trait loci analysis, supporting the concept that risk genes cluster in pathways. Using a network derived from 2,000 transcriptional profiles we identify SPDEF, ER?, FOXA1, GATA3 and PTTG1 as master regulators of fibroblast growth factor receptor 2 signalling, and show that ER? occupancy responds to fibroblast growth factor receptor 2 signalling. Our results indicate that ER?, FOXA1 and GATA3 contribute to the regulation of breast cancer susceptibility genes, which is consistent with the effects of anti-oestrogen treatment in breast cancer prevention, and suggest that fibroblast growth factor receptor 2 signalling has an important role in mediating breast cancer risk.
| S-EPMC3778544 | biostudies-literature
Project description:The fibroblast growth factor receptor 2 (FGFR2) locus is consistently the top hit in genome-wide association studies for oestrogen receptor-positive (ER(+)) breast cancer. Yet, its mode of action continues to be controversial. Here, we employ a systems biology approach to demonstrate that signalling via FGFR2 counteracts cell activation by oestrogen. In the presence of oestrogen, the oestrogen receptor (ESR1) regulon (set of ESR1 target genes) is in an active state. However, signalling by FGFR2 is able to reverse the activity of the ESR1 regulon. This effect is seen in multiple distinct FGFR2 signalling model systems, across multiple cells lines and is dependent on the presence of FGFR2. Increased oestrogen exposure has long been associated with an increased risk of breast cancer. We therefore hypothesized that risk variants should reduce FGFR2 expression and subsequent signalling. Indeed, transient transfection experiments assaying the three independent variants of the FGFR2 risk locus (rs2981578, rs35054928 and rs45631563) in their normal chromosomal context show that these single-nucleotide polymorphisms (SNPs) map to transcriptional silencer elements and that, compared with wild type, the risk alleles augment silencer activity. The presence of risk variants results in lower FGFR2 expression and increased oestrogen responsiveness. We thus propose a molecular mechanism by which FGFR2 can confer increased breast cancer risk that is consistent with oestrogen exposure as a major driver of breast cancer risk. Our findings may have implications for the clinical use of FGFR2 inhibitors.
| S-EPMC4967216 | biostudies-literature
Project description:BackgroundIt is biologically plausible that genotoxic estrogens, namely estrogen DNA adducts (EDA), have a role in breast cancer development. Support comes from three prior studies that reported elevated concentrations of EDA relative to estrogen metabolites and conjugates (EDA:EMC) in women with breast cancer relative to control women.MethodsIn postmenopausal women in the Women's Health Initiative (WHI), EDA:EMC in 191 controls was compared with findings in 194 prediagnosis urine samples from breast cancer cases. EDA:EMC determinations were by mass spectrometry as previously described, and logistic regression was employed to estimate ORs.ResultsEDA:EMC did not differ in breast cancer cases compared with controls overall [0.93 (95% confidence interval, 0.71-1.23)], with a mean (SD) of 2.3 (0.8) and 2.4 (1.1) in cases and controls, respectively. Similarly, the ratio did not differ when examined by estrogen receptor or recency of biospecimen collection prior to breast cancer.ConclusionsDespite the demonstrated genotoxic properties of certain catechol estrogens resulting in EDAs, this analysis did not provide evidence for an increased breast cancer risk in relation to an elevated EDA:EMC.ImpactThis analysis, conducted prospectively within postmenopausal women in the WHI study, suggests that a strong association between EDA:EMC and breast cancer could be ruled out, as this study was powered to detect an OR of 2.2 or greater.
| S-EPMC7541674 | biostudies-literature