Basal and therapy-driven hypoxia-inducible factor-1α confers resistance to endocrine therapy in estrogen receptor-positive breast cancer.
Basal and therapy-driven hypoxia-inducible factor-1α confers resistance to endocrine therapy in estrogen receptor-positive breast cancer.
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DOI：
10.18632/oncotarget.3257
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发表时间：
2015-04-20
期刊：
影响因子：
--
通讯作者：
Liu G
中科院分区：
文献类型：
--
作者：
Jia X;Hong Q;Lei L;Li D;Li J;Mo M;Wang Y;Shao Z;Shen Z;Cheng J;Liu G
耐药是乳腺癌内分泌治疗的一个障碍。我们测量了52例原发性乳腺癌患者在接受来曲唑新辅助内分泌治疗至少3个月前后的缺氧诱导因子(HIF)-1α水平。治疗前HIF-1α水平与阴性临床结果相关。此外，与治疗前活检样本相比，治疗后残留肿瘤中HIF-1α水平升高。在动物实验中，与对照异种移植物相比，稳定表达HIF-1α的异种移植物对氟维司汀内分泌治疗有抵抗性。此外，HIF-1α转录被唑来膦酸（一种治疗绝经后骨质疏松症的常规药物）抑制，并伴有RAS/MAPK/ERK1/2通路的明显抑制。HIF-1α是内分泌治疗耐药的决定因素，应被视为克服雌激素受体（ER）阳性乳腺癌内分泌耐药的潜在治疗靶点。此外，唑来膦酸可能通过抑制RAS/MAPK/ERK1/2通路靶向HIF-1α转录，从而克服er阳性人乳腺癌的内分泌抵抗。对于内分泌治疗失败的乳腺癌患者，应考虑将唑来膦酸作为二线治疗的临床研究，以改善乳腺癌患者的治疗效果。
Resistance is an obstacle to endocrine therapy for breast cancer. We measured levels of hypoxia-inducible factor (HIF)-1α in 52 primary breast cancer patients before and after receiving neoadjuvant endocrine therapy with letrozole for at least 3 months. Pre-treatment levels of HIF-1α were associated with negative clinical outcome. Furthermore, levels of HIF-1α were increased in post-treatment residual tumors compared with those in pre-treatment biopsy samples. In animal studies, xenografts stably expressing HIF-1α were resistant to endocrine therapy with fulvestrant compared with the effects in control xenografts. Additionally, HIF-1α transcription was inhibited by zoledronic acid, a conventional drug for the treatment of postmenopausal osteoporosis, and was accompanied by a marked inhibition of the RAS/MAPK/ERK1/2 pathway. HIF-1α is a determinant of resistance to endocrine therapy and should be considered as a potential therapeutic target for overcoming endocrine resistance in estrogen receptor (ER)-positive breast cancer. In addition, zoledronic acid may overcome endocrine resistance in ER-positive human breast cancer by targeting HIF-1α transcription through inhibition of the RAS/MAPK/ERK1/2 pathway. Clinical studies on the administration of zoledronic acid as a second line treatment in patients who failed endocrine therapy should be considered to improve therapeutic outcomes in breast cancer patients.
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DOI：
10.1111/j.1349-7006.2001.tb01064.x
发表时间：
2001-10
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Kurebayashi J;Otsuki T;Moriya T;Sonoo H
通讯作者：
Sonoo H
影响因子：
51.1
作者：
Gnant, Michael;Mlineritsch, Brigitte;Greil, Richard
通讯作者：
Greil, Richard
影响因子：
11.5
作者：
Cooper, C;Liu, GY;Watson, PH
通讯作者：
Watson, PH
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
45.3
作者：
Harvey, JM;Clark, GM;Allred, DC
通讯作者：
Allred, DC