HIF2a contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells

Abstract

The majority of breast cancers express estrogen receptor a (ERa), and most patients with ERa-positive breast cancer benefit from antiestrogen therapy. The ERa- modulator tamoxifen and ERa-downregulator fulvestrant are commonly employed antiestrogens. Antiestrogen resistance remains a clinical challenge, with few effective treatments available for patients with antiestrogen-resistant breast cancer. Hypoxia, which is intrinsic to most tumors, promotes aggressive disease, with the hypoxia-inducible transcription factors HIF1 and HIF2 regulating cellular responses to hypoxia. Here, we show that the ERa-expressing breast cancer cells MCF-7, CAMA-1, and T47D are less sensitive to antiestrogens when hypoxic. Furthermore, protein and mRNA levels of HIF2a/HIF2A were increased in a panel of antiestrogenresistant cells, and antiestrogen-exposure further increased HIF2a expression. Ectopic expression of HIF2a in MCF-7 cells significantly decreased sensitivity to antiestrogens, further implicating HIF2a in antiestrogen resistance. EGFR is known to contribute to antiestrogen resistance: we further show that HIF2a drives hypoxic induction of EGFR and that EGFR induces HIF2a expression. Downregulation or inhibition of EGFR led to decreased HIF2a levels. This positive and bilateral HIF2-EGFR regulatory crosstalk promotes antiestrogen resistance and, where intrinsic hypoxic resistance exists, therapy itself may exacerbate the problem. Finally, inhibition of HIFs by FM19G11 restores antiestrogen sensitivity in resistant cells. Targeting HIF2 may be useful for counteracting antiestrogen resistance in the clinic.