HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells.
HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells.
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DOI：
10.18632/oncotarget.7167
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发表时间：
2016-03-08
期刊：
影响因子：
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通讯作者：
Jögi A
中科院分区：
文献类型：
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作者：
Alam MW;Persson CU;Reinbothe S;Kazi JU;Rönnstrand L;Wigerup C;Ditzel HJ;Lykkesfeldt AE;Påhlman S;Jögi A
大多数乳腺癌表达雌激素受体α (estrogen receptor α, ERα)，大多数ERα阳性乳腺癌患者从抗雌激素治疗中获益。er α-调节剂他莫昔芬和er α-下调剂氟维司汀是常用的抗雌激素药物。抗雌激素抵抗仍然是一个临床挑战，很少有有效的治疗方法可用于抗雌激素抵抗乳腺癌患者。缺氧是大多数肿瘤的内在特征，可促进侵袭性疾病，缺氧诱导的转录因子HIF1和HIF2调节细胞对缺氧的反应。在这里，我们发现表达er α-的乳腺癌细胞MCF-7、CAMA-1和T47D在缺氧时对抗雌激素药物的敏感性较低。此外，在抗雌激素抵抗细胞中，HIF2α/HIF2A蛋白和mRNA水平升高，抗雌激素暴露进一步增加了HIF2α的表达。MCF-7细胞中异位表达HIF2α显著降低抗雌激素敏感性，进一步提示HIF2α参与抗雌激素抵抗。已知EGFR有助于抗雌激素抵抗：我们进一步表明，HIF2α驱动缺氧诱导EGFR，而EGFR诱导HIF2α表达。EGFR下调或抑制导致HIF2α水平降低。这种阳性和双边的HIF2-EGFR调节串扰促进抗雌激素抵抗，并且在存在内在缺氧抵抗的情况下，治疗本身可能加剧问题。最后，FM19G11抑制hfs可恢复耐药细胞的抗雌激素敏感性。在临床上，靶向HIF2可能有助于对抗抗雌激素抵抗。
The majority of breast cancers express estrogen receptor α (ERα), and most patients with ERα-positive breast cancer benefit from antiestrogen therapy. The ERα-modulator tamoxifen and ERα-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 ERα-expressing breast cancer cells MCF-7, CAMA-1, and T47D are less sensitive to antiestrogens when hypoxic. Furthermore, protein and mRNA levels of HIF2α/HIF2A were increased in a panel of antiestrogen-resistant cells, and antiestrogen-exposure further increased HIF2α expression. Ectopic expression of HIF2α in MCF-7 cells significantly decreased sensitivity to antiestrogens, further implicating HIF2α in antiestrogen resistance. EGFR is known to contribute to antiestrogen resistance: we further show that HIF2α drives hypoxic induction of EGFR and that EGFR induces HIF2α expression. Downregulation or inhibition of EGFR led to decreased HIF2α 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.