Basal and therapy-driven hypoxia-inducible factor-1α confers resistance to endocrine therapy in estrogen receptor-positive breast cancer.
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.
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Xiaoqing
X
Jia
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Qi
Q
Hong
Department of Breast Surgery, The First People's Hospital of Kunming, Kunming, P.R. China.
Li
L
Lei
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Daqiang
D
Li
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Jianwei
J
Li
Clinical Statistics Center, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Miao
M
Mo
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Yujie
Y
Wang
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Zhimin
Z
Shao
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Zhenzhou
Z
Shen
Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University Shanghai, P.R. China.
Jingyi
J
Cheng
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China.
Guangyu
G
Liu
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004967:Estrogens; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000077289:Letrozole; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D017698:Postmenopause; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000032:analysis*; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
D018931:Antineoplastic Agents, Hormonal; D004164:Diphosphonates; D004967:Estrogens; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D009363:Neoplasm Proteins; D009570:Nitriles; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D014230:Triazoles; D000077267:Fulvestrant; D004958:Estradiol; D000077211:Zoledronic Acid; D000077289:Letrozole
HIF-1a; breast cancer; endocrine resistance; estrogen receptor; zoledronic acid