HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells

Alam, Muhammad Wasi; Persson, C.; Reinbothe, Susann; Kazi, Julhash U.; Wigerup, Caroline; Ditzel, Henrik J.; Lykkesfeldt, Annè E.; Påhlman, Sven; Jögi, Annika

doi:10.18632/oncotarget.7167

Cited by 18 publications

(19 citation statements)

References 46 publications

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“…We acknowledge our in vitro data may have limitations as this was generated from a single cell line, MCF-7 and its isogenic tamoxifen-resistant variant developed in house over 21 months [29, 30]. Nevertheless this is consistent with other work in this field where MCF- 7 is widely regarded as the most suitable cell line to study tamoxifen resistance due to its expression of ERα and exquisite hormone sensitivity in vitro [31], with recent publications using single MCF-7 derivatives [32, 33]. …”

Section: Discussionsupporting

confidence: 67%

Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancerin vitro

et al. 2016

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Tamoxifen (TAM) remains the adjuvant therapy of choice for pre-menopausal women with ERα-positive breast cancer. Resistance and recurrence remain, however, a major challenge with many women relapsing and subsequently dying. The insulin-like growth factor (IGF) axis is involved in breast cancer pathogenesis and progression to endocrine resistant disease, but there is very little data on the expression and potential role of IGF-binding proteins (IGFBP) during acquisition of the resistant phenotype. The aim of this study was to determine the expression and functional role of IGFBP-2 and -5 in the development of TAM resistance (TamR) in vitro and to test retrospectively whether they were predictive of resistance in a tissue microarray of 77 women with primary breast cancers who relapsed on/after endocrine therapy and 193 who did not with long term follow up. Reciprocal expression of IGFBP-2 and IGFBP-5 was observed at both mRNA and protein level in TamR cells. IGFBP-2 expression was increased by 10-fold while IGFBP-5 was decreased by 100-fold, compared to TAM-sensitive control cells. shRNA-mediated silencing of IGFBP-2 in TamR cells restored TAM sensitivity suggesting a causal role for this gene in TamR. While silencing of IGFBP-5 in control cells had no effect on TAM sensitivity, it significantly increased the migratory capacity of these cells. Quantitative image analysis of immunohistochemical data failed, however, to demonstrate an effect of IGFBP2 expression in endocrine-relapsed patients. Likewise, IGFBP-2 and IGFBP-5 expression failed to show any significant associations with survival either in patients relapsing or those not relapsing on/after endocrine therapy. By contrast, in silico mining of a separate published dataset showed that in patients who received endocrine treatment, loss of expression of IGBP-5 was significantly associated with worse survival. Overall these data suggest that co-ordinated and reciprocal alteration in IGFBP-2 and −5 expression may play a role in the acquisition of endocrine resistance.

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Section: Discussionsupporting

confidence: 67%

Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancerin vitro

et al. 2016

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“…5 J and K). The fact that HIF-2α expression also occurred in ∼26% of ER − tumors with absent or low FOXA1 suggests additional regulatory mechanisms of HIF-2α activation, possibly via high GFR-related signaling (40), as also shown in neuroblastoma (41).…”

Section: Activation Of Se Formation Is Correlated With Reprogrammed Fmentioning

confidence: 71%

“…However, we show that HIF-2α up-regulation is concordant with H-FOXA1 across our multiple endocrine-resistant cell models grown under nonhypoxic conditions. Noticeably, high GFR-related signaling, such as EGFR, has been shown to induce HIF-2α expression in endocrine-resistant BC cells (40). Therefore, both H-FOXA1-induced SEs and high GFR-related signaling (10), which also activates FOXA1, may converge to activate HIF-2α transcription and signaling in endocrine-resistant BC.…”

Section: Discussionmentioning

confidence: 99%

FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer

Pereira

Angelis

et al. 2019

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

111

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Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER+) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER+breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER+/HER2−metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with theESR1mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α–dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.

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“…These findings demonstrate that HIF-2α can enhance the stemness phenotype of breast cancer cells to induce resistance to PTX. Alam et al reported that HIF-2α contributed to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells [ 32 ]. However, mechanisms in the resistance of breast cancer cells to PTX induced by HIF-2α remain unclear.…”

Section: Discussionmentioning

confidence: 99%

HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways

Yan

Liu

Liang

et al. 2018

J Exp Clin Cancer Res

137

107

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BackgroundHypoxic tumor microenvironment and maintenance of stemness contribute to drug resistance in breast cancer. However, whether Hypoxia-inducible factor-2α (HIF-2α) in hypoxic tumor microenvironment mediates conversion to a stem cell phenotype and chemoresistance of breast tumors has not been elucidated.MethodsThe mRNA and protein expressions of HIF-1α, HIF-2α, Wnt and Notch pathway were determined using qRT-PCR and western blot. Cell viability and renew ability were assessed by MTT, Flow cytometric analysis and soft agar colony formation.ResultsIn our study, acute hypoxia (6–12 h) briefly increased HIF-1α expression, while chronic hypoxia (48 h) continuously enhanced HIF-2α expression and induced the resistance of breast cancer cells to Paclitaxel (PTX). Furthermore, HIF-2α overexpression induced a stem cell phenotype, the resistance to PTX and enhanced protein expression of stem cell markers, c-Myc, OCT4 and Nanog. Most importantly, Wnt and Notch signaling, but not including Shh, pathways were both activated by HIF-2α overexpression. Dickkopf-1 (DKK-1), a Wnt pathway inhibitor, and L685,458, an inhibitor of the Notch pathway, reversed the resistance to PTX and stem phenotype conversion induced by HIF-2α overexpression. In addition, HIF-2α overexpression enhanced tumorigenicity and resistance of xenograft tumors to PTX, increased activation of the Wnt and Notch pathways and induced a stem cell phenotype in vivo.ConclusionIn conclusion, HIF-2α promoted stem phenotype conversion and induced resistance to PTX by activating Wnt and Notch pathways.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0925-x) contains supplementary material, which is available to authorized users.

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HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells

Cited by 18 publications

References 46 publications

Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancerin vitro

Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancerin vitro

FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer

HIF-2α promotes conversion to a stem cell phenotype and induces chemoresistance in breast cancer cells by activating Wnt and Notch pathways

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