Abstract
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.
Keywords:
HIF-1a; breast cancer; endocrine resistance; estrogen receptor; zoledronic acid.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Hormonal / pharmacology*
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Antineoplastic Agents, Hormonal / therapeutic use
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Cell Hypoxia
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Cell Line, Tumor
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Diphosphonates / pharmacology
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Diphosphonates / therapeutic use*
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / physiology*
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Estradiol / analogs & derivatives
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Estradiol / pharmacology
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Estradiol / therapeutic use
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Estrogens*
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Female
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Fulvestrant
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
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Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
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Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
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Imidazoles / pharmacology
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Imidazoles / therapeutic use*
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Letrozole
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Mice
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Mice, Nude
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Neoadjuvant Therapy
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Neoplasm Proteins / analysis
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / physiology*
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Neoplasms, Hormone-Dependent / drug therapy
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Neoplasms, Hormone-Dependent / metabolism
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Neoplasms, Hormone-Dependent / pathology*
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Neovascularization, Pathologic / drug therapy
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Nitriles / pharmacology
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Nitriles / therapeutic use
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Postmenopause
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RNA Interference
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RNA, Small Interfering / genetics
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Receptors, Estrogen / analysis*
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Transcription, Genetic / drug effects
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Treatment Outcome
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Triazoles / pharmacology
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Triazoles / therapeutic use
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Xenograft Model Antitumor Assays
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Zoledronic Acid
Substances
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Antineoplastic Agents, Hormonal
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Diphosphonates
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Estrogens
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Imidazoles
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Neoplasm Proteins
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Nitriles
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RNA, Small Interfering
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Receptors, Estrogen
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Triazoles
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Fulvestrant
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Estradiol
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Zoledronic Acid
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Letrozole