Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer

Yamamoto, Yutaka; Ibusuki, Mutsuko; Okumura, Yasuhiro; Kawasoe, Teru; Kai, Kazuharu; Iyama, Ken‐ichi; Iwase, Hirotaka

doi:10.1007/s10549-007-9742-1

Cited by 136 publications

(106 citation statements)

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“…Under hypoxia, HIF-1a subunit is stabilized and dimerizes with HIF-1b, translocates to the nucleus, and activates transcription of target genes via binding to hypoxia-responsive elements (HREs) [22,28]. HIF-1 induces the expression of more than 100 genes [29], including the vascular endothelial growth factor (VEGF), glycolytic enzymes [30], and various genes involved in proliferation and cell cycle progression, to insure the cancer cell survival [20,31,32]. Recently, the HIF-1 role as a repressor in response to hypoxia has been shown in several tumors.…”

Section: Introductionmentioning

confidence: 99%

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Fanale

Bazan

Corsini

et al. 2013

Breast Cancer Res Treat

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Numerous microarray-based gene expression studies performed on several types of solid tumors revealed significant changes in key genes involved in progression and regulation of the cell cycle, including AURKA that is known to be overexpressed in many types of human malignancies. Tumor hypoxia is associated with poor prognosis in several cancer types, including breast cancer (BC). Since hypoxia is a condition that influences the expression of many genes involved in tumorigenesis, proliferation, and cell cycle regulation, we performed a microarray-based gene expression analysis in order to identify differentially expressed genes in BC cell lines exposed to hypoxia. This analysis showed that hypoxia induces a down-regulation of AURKA expression. Although hypoxia is a tumor feature, the molecular mechanisms that regulate AURKA expression in response to hypoxia in BC are still unknown. For the first time, we demonstrated that HIF-1 activation downstream of hypoxia could drive AURKA down-regulation in BC cells. In fact, we found that siRNA-mediated knockdown of HIF-1a significantly reduces the AURKA down-regulation in BC cells under hypoxia. The aim of our study was to obtain new insights into AURKA transcriptional regulation in hypoxic conditions. Luciferase reporter assays showed a reduction of AURKA promoter activity in hypoxia. Unlike the previous findings, we hypothesize a new possible mechanism where HIF-1, rather than inducing transcriptional activation, could promote the AURKA down-regulation via its binding to hypoxia-responsive elements into the proximal region of the AURKA promoter. The present study shows that hypoxia directly links HIF-1 with AURKA expression, suggesting a possible pathophysiological role of this new pathway in BC and confirming HIF-1 as an important player linking an environmental signal to the AURKA promoter. Since AURKA down-regulation overrides the estrogen-mediated growth and chemoresistance in BC cells, these findings could be important for the development of new possible therapies against BC.

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Section: Introductionmentioning

confidence: 99%

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Fanale

Bazan

Corsini

et al. 2013

Breast Cancer Res Treat

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“…Furthermore, high HIF-1α levels are associated with hormone receptor negativity. HER-2 over expression increased levels of vascular endothelial cell growth factor (VEGF), cyclo-oxygenase-2 (COX-2) and nuclear p53, indicating a close link between HIF-1α and aggressive phenotypes in breast cancer (28) . Dale and co-workers (10) described the presence of different HIF-1α splice variants in human breast cancer and non-malignant tissue samples.…”

Section: Introductionmentioning

confidence: 99%

Prognostic and predictive biomarkers for hypoxic regions on breast cancer: advances and challenges

Rêgo¹,

Beltrão²

2013

J. Bras. Patol. Med. Lab.

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Hypoxia has been extensively studied in solid tumors mainly in breast cancers and it is commonly associated with chemotherapy and radiotherapy resistance. Hypoxia inducible factor (HIF)-1α is responsible for hypoxia in the tumor microenvironment and its molecular mechanisms as well as its therapeutic strategies have been described. However, a few investigations in the literature deal with its role in the hypoxic environment at diagnosis with the aim to guide therapeutic approaches. This study alerts researchers in pathology and oncology to the importance of assessing area extension as well as specific biomarkers, inasmuch as molecules reactive to hypoxia may indicate response to antiangiogenic therapy. The extension of hypoxic areas may alter the choice of therapeutic approach, insofar as some antiangiogenic treatments may considerably aggravate patient's clinical course since they create a hypoxic environment.

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“…HIF-1α levels are significantly higher in invasive and poorly differentiated breast cancers as compared to well-differentiated cancers [233,319,320]. Specifically, increased levels of HIF-1α mRNA and the core hypoxic transcriptional response are associated with hormone receptor negative breast cancers [92,320].…”

Section: Which Additional Studies Can Be Performed To Better Define Tmentioning

confidence: 98%

“…Indeed, HIF-1α is overexpressed in many human cancers (reviewed in [25]), and over-expression in breast tumors predicts relapse and indicates a higher risk of metastasis [85]. HIF-1α levels are significantly higher in invasive and poorly differentiated breast cancers as compared to well-differentiated cancers [233,319,320]. Specifically, increased levels of HIF-1α mRNA and the core hypoxic transcriptional response are associated with hormone receptor negative breast cancers [92,320].…”

Section: Which Additional Studies Can Be Performed To Better Define Tmentioning

confidence: 99%

“…Overexpression and enhanced activity of HIFα subunits is common in a variety of cancer types and has been shown to be a key mediator of tumor formation and progression [85,95,320]. Previous studies showed that tumors derived from MDA-MB-231 cells that lack HIF-1α and HIF-2α displayed significantly decreased growth relative to wildtype controls [71,292,293].…”

Section: Ectopic Brk Expression Enhances Growth Of Hif1a/hif2a Knockomentioning

confidence: 99%

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Identification of Novel HIF1A Target Genes That Regulate Tumor Progression and Metastasis

Peacock¹

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DEDICATION ABSTRACTHypoxia is a hallmark of most solid tumors. In response to hypoxic stress tumor cells adapt by regulating survival, metabolism and angiogenesis. The heterodimeric Hypoxia-Inducible Factor (HIF) transcription factors are the master regulators of this response. HIFs play key roles in many critical aspects of cancer biology including angiogenesis, stem cell maintenance, metabolic reprogramming, invasion, metastasis and resistance to radiation therapy and chemotherapy. Overexpression of HIF-1α and HIF-2α has been documented in multiple human cancers and HIF-1α protein is over-expressed in ~30% of primary breast tumors and ~70% of metastases, which independently correlates with poor prognosis and decreased survival in patients. A precise role for HIF-2α in breast cancer is still being elucidated.Our lab has established primary mammary tumor epithelial cells (MTECs) from late stage carcinomas originating in PyMT+; Hif1a floxed mice. These MTECs were exposed to either Adenovirus-beta-gal or -Cre to create wild-type (WT) and knockout (KO) cells, respectively. Deletion of HIF-1 activity reduced primary tumor growth by ~60% and the formation of lung macrometastases originating from mammary fat pad tumors by >90%. In addition, deletion of Hif1a reduced mammary tumorsphere formation efficiency (TSE) in vitro and tumor initiating cell (TIC) frequency in vivo. In contrast, in triple negative models of breast cancer, knockdown of HIF1A had the opposite phenotype, increasing TSE in vitro and increased primary mammary tumor growth in vivo. ITGA6 (CD49f) was identified as one HIF-1α-dependent cancer stem cell marker that enriches for both primary mammary tumor growth and metastasis to the lung. Microarray profiling conducted to identify genes differentially expressed between PyMT WT and KO cells and end-stage WT and KO tumors revealed several genes that were down-regulated in both data sets in response to deletion of Hif1a. One mRNA of particular interest, creatine kinase brain isoform (Ckb) was down-regulated in KO cells >100 fold and >2 fold in end-stage tumors. Transplantation of Ckb knockdown (KD) PyMT cells to the mammary fat pad delayed initiation of palpable tumors by >30 days. When cells were introduced into the circulation via tail vein injection, 20% of mice injected with Ckb KD cells developed lung metastases whereas 100% of mice injected with WT cells developed metastases. Likewise, when mice injected with WT PyMT cells were treated daily with a CKB chemical inhibitor, cyclocreatine (cCr), lungs of vehicle treated (saline) mice were almost completely covered with surface metastases, while lungs of cCr treated mice contained very few metastases.Overall, our data show that HIF-1α strongly promotes mammary tumor initiation, progression and metastasis, in part through regulation of TIC activity. Metastasis is the major cause of mortality in breast cancer patients. Further characterization of the distinct roles of HIF-1α versus HIF-2α in breast cancer and metastasis, and genes downstream of the HIFs, suc...

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Hypoxia-inducible factor 1α is closely linked to an aggressive phenotype in breast cancer

Abstract: These findings suggest that HIF-1alpha was closely linked to an aggressive phenotype in breast cancer. It may be useful to study the expression of HIF-1alpha using immunohistochemical analysis for better understanding of the tumor characteristics of breast cancer.

Cited by 136 publications

References 40 publications

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Prognostic and predictive biomarkers for hypoxic regions on breast cancer: advances and challenges

Identification of Novel HIF1A Target Genes That Regulate Tumor Progression and Metastasis

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