Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

Stiehl, Daniel P.; Bordoli, Mattia R; Abreu-Rodríguez, Irene; Wollenick, Kristin; Schraml, Peter; Gradin, Katarina; Poellinger, Lorenz; Kristiansen, Glen; Wenger, Roland H.

doi:10.1038/onc.2011.417

Cited by 69 publications

(113 citation statements)

References 50 publications

(61 reference statements)

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“…Furthermore, HIF1A expression showed progressive induction in breast tumors from grade 1 to grade 3, and HIF2A (EPAS1) expression showed the opposite (Fig. 1B); this result is consistent with the antagonistic relationship between HIF1-α and HIF2-α reported previously in breast cancer (34). These observations indicate that the differential regulation of Ezh2 and PRC2 function in different subtypes of breast cancer might be associated with HIF1-α and that the up-regulation of Ezh2 in TNBC may implicate a PRC2-independent function, supporting previously reported non-PRC2 activity of Ezh2 in TNBC (8,13).…”

Section: Resultssupporting

confidence: 80%

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Mahara

Lee

Feng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Despite the established oncogenic function of Polycomb repressive complex 2 (PRC2) in human cancers, its role as a tumor suppressor is also evident; however, the mechanism underlying the regulation of the paradoxical functions of PRC2 in tumorigenesis is poorly understood. Here we show that hypoxia-inducible factor 1, α-subunit (HIFI-α) is a crucial modulator of PRC2 and enhancer of zeste 2 (EZH2) function in breast cancer. Interrogating the genomic expression of breast cancer indicates high HIF1A activity correlated with high EZH2 expression but low PRC2 activity in triple-negative breast cancer compared with other cancer subtypes. In the absence of HIFIA activation, PRC2 represses the expression of matrix metalloproteinase genes (MMPs) and invasion, whereas a discrete Ezh2 complexed with Forkhead box M1 (FoxM1) acts to promote the expression of MMPs. HIF1-α induction upon hypoxia results in PRC2 inactivation by selective suppression of the expression of suppressor of zeste 12 protein homolog (SUZ12) and embryonic ectoderm development (EED), leading to a functional switch toward Ezh2/FoxM1-dependent induction of the expression of MMPs and invasion. Our study suggests a tumor-suppressive function of PRC2, which is restricted by HIF1-α, and an oncogenic function of Ezh2, which cooperates with FoxM1 to promote invasion in triple-negative breast cancer.

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Section: Resultssupporting

confidence: 80%

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Mahara

Lee

Feng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Stable knockdown of HIF-1 α and HIF-2 α in HEK293 cells by RNA interference was achieved by lentiviral transduction of short hairpin (shRNA) constructs. Viral particles were produced in HEK293T human enbryonic kidney cells using the ViraPower lentiviral expression system according to the manufacturer ' s protocol (Invitrogen, Basel, Switzerland) as described previously (Stiehl et al, 2012).…”

Section: Cell Culture and Lentiviral Transductionmentioning

confidence: 99%

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

Wrann

Kaufmann²,

Wirthner³

et al. 2013

Biological Chemistry

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Abstract:The histone variant 2AX (H2AX) is phosphorylated at Serine 139 by the PI3K-like kinase family members ATM, ATR and DNA-PK. Genotoxic stress, such as tumor radioand chemotherapy, is considered to be the main inducer of phosphorylated H2AX ( γ H2AX), which forms distinct foci at sites of DNA damage where DNA repair factors accumulate. γ H2AX accumulation under severe hypoxic/anoxic (0.02 % oxygen) conditions has recently been reported to follow replication fork stalling in the absence of detectable DNA damage. In this study, we found HIF-dependent accumulation of γ H2AX in several cancer cell lines and mouse embryonic fibroblasts exposed to physiologically relevant chronic hypoxia (0.2 % oxygen), which did not induce detectable levels of DNA strand breaks. The hypoxic accumulation of γ H2AX was delayed by the RNAi-mediated knockdown of HIF-1 α or HIF-2 α and further decreased when both HIF-α s were absent. Conversely, basal phosphorylation of H2AX was increased in cells with constitutively stabilized HIF-2 α . These results suggest that both HIF-1 and HIF-2 are involved in γ H2AX accumulation by tumor hypoxia, which might increase a cancer cell ' s capacity to repair DNA damage, contributing to tumor therapy resistance.

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“…Recent studies have proposed that while HIF-1 controls the acute or immediate response to hypoxia during tumor development, HIF-2 may be responsible for the prolonged hypoxic response [26]. Furthermore, there is evidence indicating the role that HIF-1 or HIF-2 plays within tumors depends on their opposing regulation of MYC transcriptional activity [94].…”

Section: Hifs Role In Breast Cancermentioning

confidence: 99%

“…Although HIF-1α was previously hypothesized to be the predominant regulator of the hypoxic response in breast cancer cells [1, 22,26], emerging evidence also indicates that HIF-2α may also play a role in breast cancer growth, as will be further discussed in Chapter 4. Recent studies have proposed that while HIF-1 controls the acute or immediate response to hypoxia during tumor development, HIF-2 may be responsible for the prolonged hypoxic response [26].…”

Section: Hifs Role In Breast Cancermentioning

confidence: 99%

“…While many of these genes can be regulated by either HIF-1 or HIF-2, some genes rely more heavily on one HIFα subunit or the other. For example the genes carbonic anhydrase 9 (CA9) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) are more dependent upon HIF-1 activity, whereas epidermal growth factor (EGFR) and WNT1-inducible signaling pathway protein-2 (WISP2) depend more on HIF-2 regulated transcription [26]. In addition to canonical HIF target mRNAs, the HIFs are also known to be involved in microRNA (miRNA) regulation [27].…”

Section: Regulation Of Hypoxia Inducible Factors (Hifs)mentioning

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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Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG–EGFR/ErbB4 autocrine loop

Cited by 69 publications

References 50 publications

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

HIF mediated and DNA damage independent histone H2AX phosphorylation in chronic hypoxia

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

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