Hypoxia-inducible factor 1α in breast cancer prognosis

Wang, Wei; He, Yong; Sun, Qing‐Fu; Wang, Yong; Han, Xinghua; Peng, Deng-fu; Yao, Yiming; Ji, Cheng; Hu, Bing

doi:10.1016/j.cca.2013.10.018

Cited by 34 publications

(33 citation statements)

References 31 publications

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“…Previous laboratory and clinical reports showed that HIF1A expression is associated with HR-negative status (Trastour et al, 2007;Wolff et al, 2017). However, our finding is somewhat contradictive to the recent meta-analysis which concludes that high HIF1A expression is an indicator of poor prognosis, even though significant heterogeneity did exist in this meta-analysis (to OS, n = 7 studies, 1,608 patients; to PFS, n = 8 studies, 1,217 patients) (Wang et al, 2014). This discrepancy may occur largely due to our limited sample number and our limited focus on treatment-naïve advanced stages only.…”

Section: Discussioncontrasting

confidence: 99%

“…Recent meta-analyses showed that HIF1A (Wang et al, 2014) and CAIX (van Kuijk et al, 2016) overexpression are predictive of poor prognosis. However, all studies in those meta-analyses employed immunohistochemistry (IHC) to assess protein expression of HIF1A and CAIX, which is regarded as semi-quantitative method and subject to a certain degree of inter-and even intra-observer variability which makes scoring prone to discordance.…”

Section: The Hypoxic Response Expression As a Survival Biomarkers In mentioning

confidence: 99%

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The Hypoxic Response Expression as a Survival Biomarkers in Treatment-Naive Advanced Breast Cancer

Gunawan

Hatta²,

Benyamin³

et al. 2020

Asian Pac J Cancer Prev

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Objective: Hypoxia-associated biomarkers profiling may provide information for prognosis, staging, and subsequent therapy. We aim to evaluate whether the quantitative gene and protein expression of hypoxic response tumor markers-carbonic anhydrase IX (CAIX) and hypoxia-inducible factor 1 alpha (HIF1A)-may have a role in predicting survival in advanced breast cancer of Indonesian population. Methods: Tumor tissues and peripheral blood samples were collected from treatment-naïve locally advanced (LABC) or metastatic breast cancer patients (MBC) at Wahidin Sudirohusodo General Hospital (Makassar, South Sulawesi) and its referral network hospitals from July 2017 to March 2019. The level of mRNA (of blood and tumor tissue samples) and soluble protein (of blood samples) of CAIX and HIF1A were measured by RT-qPCR and ELISA methods, respectively, besides the standard histopathological grading and molecular subtype assessment. The CAIX and HIF1A expression, patients' age, tumor characteristics, surgery status, and neoadjuvant chemotherapy drug classes were further involved in survival analyses for overall survival (OS) and progression-free survival (PFS). Results: Forty (30 LABC, 10 MBC) eligible patients examined were 21 hormone-receptors positives (15 Luminal A, 6 Luminal B) and 19 hormone-receptors negatives (10 HER2-enriched, 9 triple-negative). The CAIX blood mRNA and CAIX soluble protein levels in hormone-receptors negative patients were higher than in hormone-receptor-positive patients (p < 0.05). In univariate analysis, both CAIX and HIF1A levels predict OS (except HIF1A protein) with CAIX tissue mRNA has the highest hazard ratio (HR 8.04, 95%CI:2.45-26.39), but not PFS. Cox proportional hazard model confirmed that CAIX tissue mRNA is the independent predictor of OS (HR 6.10, 95%CI: 1.16-32.13) along with surgical status and tumor advancement type (LABC or MBC). Conclusions: CAIX mRNA expression of tumor tissue in treatment-naïve advanced breast cancer has a predictive value for OS.

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Section: Discussioncontrasting

confidence: 99%

Section: The Hypoxic Response Expression As a Survival Biomarkers In mentioning

confidence: 99%

The Hypoxic Response Expression as a Survival Biomarkers in Treatment-Naive Advanced Breast Cancer

Gunawan

Hatta²,

Benyamin³

et al. 2020

Asian Pac J Cancer Prev

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“…Hypoxia-inducible factor 1-alpha (HIF1A) is a key regulator of the hypoxia response and has been linked to breast cancer progression [39]. In our binding site enrichment analysis, we observed that HIF1A binding sites are strongly depleted in MDA-MB-231 DEGs although HIF1A has a very high expression in this cell line.…”

Section: Discussionmentioning

confidence: 66%

Integrated RNA-seq and DNase-seq analyses identify phenotype-specific BMP4 signaling in breast cancer

et al. 2017

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BackgroundBone morphogenetic protein 4 (BMP4) plays an important role in cancer pathogenesis. In breast cancer, it reduces proliferation and increases migration in a cell line-dependent manner. To characterize the transcriptional mediators of these phenotypes, we performed RNA-seq and DNase-seq analyses after BMP4 treatment in MDA-MB-231 and T-47D breast cancer cells that respond to BMP4 with enhanced migration and decreased cell growth, respectively.ResultsThe RNA-seq data revealed gene expression changes that were consistent with the in vitro phenotypes of the cell lines, particularly in MDA-MB-231, where migration-related processes were enriched. These results were confirmed when enrichment of BMP4-induced open chromatin regions was analyzed. Interestingly, the chromatin in transcription start sites of differentially expressed genes was already open in unstimulated cells, thus enabling rapid recruitment of transcription factors to the promoters as a response to stimulation. Further analysis and functional validation identified MBD2, CBFB, and HIF1A as downstream regulators of BMP4 signaling. Silencing of these transcription factors revealed that MBD2 was a consistent activator of target genes in both cell lines, CBFB an activator in cells with reduced proliferation phenotype, and HIF1A a repressor in cells with induced migration phenotype.ConclusionsIntegrating RNA-seq and DNase-seq data showed that the phenotypic responses to BMP4 in breast cancer cell lines are reflected in transcriptomic and chromatin levels. We identified and experimentally validated downstream regulators of BMP4 signaling that relate to the different in vitro phenotypes and thus demonstrate that the downstream BMP4 response is regulated in a cell type-specific manner.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3428-1) contains supplementary material, which is available to authorized users.

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“…Breast cancer often manifests as solid hypoxic tumors which are associated with high levels of hypoxia-inducible factor (HIF)-α and a poor prognosis. [1][2][3][4] The HIF protein consists of an oxygen-sensitive α subunit and a constitutively expressed β subunit that regulate the expression of target genes. 5,6 HIF-1α and HIF-2α are the best-characterized α subunits of HIFs.…”

Section: Introductionmentioning

confidence: 99%

Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

Hait

Maiti

et al. 2020

FASEB j.

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Sphingosine kinase 2 (SphK2) is known to phosphorylate the nuclear sphingolipid metabolite to generate sphingosine‐1‐phosphate (S1P). Nuclear S1P is involved in epigenetic regulation of gene expression; however, the underlying mechanisms are not well understood. In this work, we have identified the role of nuclear S1P and SphK2 in regulating hypoxia‐responsive master transcription factors hypoxia‐inducible factor (HIF)‐1α/2α, and their functions in breast cancer, with a focus on triple‐negative breast cancer (TNBC). We have shown SphK2 is associated with HIF‐1α in protein complexes, and is enriched at the promoters of HIF target genes, including vascular endothelial growth factor (VEGF), where it enhances local histone H3 acetylation and transcription. S1P specifically binds to the PAS domains of HIF‐1α. SphK2, and HIF‐1α expression levels are elevated in metastatic estrogen receptor‐positive (ER+) and TNBC clinical tissue specimens compared to healthy breast tissue samples. To determine if S1P formation in the nucleus by SphK2 is a key regulator of HIF functions, we found using a preclinical TNBC xenograft mouse model, and an existing selective SphK2 inhibitor K‐145, that nuclear S1P, histone acetylation, HIF‐1α expression, and TNBC tumor growth were all reduced in vivo. Our results suggest that S1P and SphK2 in the nucleus are linked to the regulation of HIF‐1α/2α functions associated with breast cancer progression, and may provide potential therapeutic targets.

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Hypoxia-inducible factor 1α in breast cancer prognosis

Cited by 34 publications

References 31 publications

The Hypoxic Response Expression as a Survival Biomarkers in Treatment-Naive Advanced Breast Cancer

The Hypoxic Response Expression as a Survival Biomarkers in Treatment-Naive Advanced Breast Cancer

Integrated RNA-seq and DNase-seq analyses identify phenotype-specific BMP4 signaling in breast cancer

Regulation of hypoxia‐inducible factor functions in the nucleus by sphingosine‐1‐phosphate

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