Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

Abstract

The involvement of estrogen (E2) and hypoxia in tumor progression is well established. Hypoxia has been reported to activate and degrade estrogen receptor alpha (ERα) in breast cancer cells. Furthermore, E2 has been shown to regulate hypoxia-inducible factor (HIF)-1α protein, but its role in HIF-2α regulation remains largely unexplored. In this study, we found that both HIF-2α mRNA and protein were down-regulated in ER positive but not ER negative breast cancer cells upon treatment with E2. The analysis of 690 samples derived from 608 mixed and 82 triple-negative breast cancer patients revealed that high nuclear HIF-2α tumor levels are associated with a worse prognosis specifically in human epidermal growth factor receptor 2 (HER2) and hormone receptor positive patients. Consistently, ERα/HER2 positive breast cancer cells displayed less pronounced downregulation of HIF-2α by E2. Experiments using a histone deacetylase inhibitor indicate that the E2 mediated decrease in HIF-2α mRNA is due to transcriptional repression. A functional estrogen response element (ERE) was identified in the first intron of the gene encoding HIF-2α (EPAS1), suggesting transcriptional co-repressor recruitment by ERα. Our results demonstrate a novel modulation of HIF-2α in breast cancer cells, explaining the opposing regulation between HIF-1α and HIF-2α in hormone-responsive breast cancer.

Prognostic Role of Hypoxia-Inducible Factor-2α Tumor Cell Expression in Cancer Patients: A Meta-Analysis

“…A total of 38 from the selected 49 studies investigated the association between HIF-2α and OS. All the necessary information to estimate the HR could not be obtained from two papers and were therefore not included in the analysis (Table S1 in Supplementary Material) ( 21 , 23 , 24 , 26 – 31 , 33 – 35 , 37 – 39 , 41 – 43 , 45 , 46 , 48 , 49 , 51 , 52 , 54 – 57 , 59 , 60 , 62 – 69 ). Based on these studies, high HIF-2α expression was statistically significantly associated with a decreased OS (HR = 1.69, 95% CI 1.39–2.06, p < 0.0001, Figure 3 ).…”

“… Forest plot of hazard ratios (HRs) with 95% confidence interval (95% CI) (horizontal bars) for the association of hypoxia-inducible factor-2α expression and overall survival (OS). Symbol size represents the assigned weight of the study ( 21 , 24 , 26 , 28 , 30 , 31 , 33 – 35 , 37 , 38 , 41 – 43 , 45 , 46 , 48 , 49 , 52 , 54 – 57 , 59 , 60 , 62 – 64 , 66 – 69 ). …”

pVHL‐mediated degradation of HIF‐2α regulates estrogen receptor α expression in normoxic breast cancer cells

“…More recently, Fuady et al . reported that HIF‐2α expression is downregulated in ERα‐positive, but not ERα‐negative, breast cancer cells in the presence of E2 and that ERα expression inversely correlates with HIF‐2α expression in tamoxifen‐treated breast cancer patients. Additionally, it has been reported that maintaining a HIF‐2α‐dominated phenotype could offer a novel approach in breast cancer therapy .…”

Comparison of the Expression Intensity of Estrogen Receptor Marker in Oral and Cutaneous Pemphigus Vulgaris

“…Estrogen affects different cells through interaction with estrogen receptors (ERs): ERα and ERβ, which belong to the family of nuclear hormone receptors. (4) In addition to the regulatory effect on human physiology, estrogen also influences diverse pathophysiological processes including cancer. (4)(5)(6) It has been proposed that female sex hormones indirectly act on the oral cavity and other tissues by up-regulation of VEGF production in macrophages and endothelial cells.…”

“…(4) In addition to the regulatory effect on human physiology, estrogen also influences diverse pathophysiological processes including cancer. (4)(5)(6) It has been proposed that female sex hormones indirectly act on the oral cavity and other tissues by up-regulation of VEGF production in macrophages and endothelial cells. (7) Some researchers have reported that ERα is mostly found in classical target tissues of estrogen such as the mammary gland and endometrium, while ERβ can be found in tissues such as colon and prostate epithelium.…”