title: Activation of hypoxia-inducible factor-1α by prolonged in vivo hyperinsulinemia treatment potentiates cancerous progression in estrogen receptor-positive breast cancer cells.
abstract: Despite numerous epidemiological data linking type 2 diabetes mellitus (T2DM) and breast cancer (BCa), there is limited experimental evidence of this association. The clinically relevant question is at what stage diabetes may exert its tumor-promoting activity. Moreover, identification of major pathophysiological pathways underlying this activity should provide valuable information for treatment. In the present study, the BCa cells isolated from long-term T2DM-treated tumors from diabetic nude mice were found to have increased cell proliferation, invasiveness and docetaxel (DTX) resistance. Importantly, this stimulatory effect was only observable in estrogen receptor (ER)-positive BCa cells. Mechanistically, T2DM-elicited hyperinsulinemia induced HIF-1α expression by reducing its ubiquitination, which was accompanied with upregulated oxidative stress. Furthermore, in vivo inhibition of HIF-1α expression effectively reversed the above-mentioned tumor-promoting activity and partially attenuated T2DM-elicited oxidative stress. Altogether, the results provide novel and compelling experimental evidence that (i) prolonged exposure to T2DM promotes BCa progression; (ii) the hyperinsulinemia/HIF-1α/oxidative stress cascade is the major mediator of this effect.
authors.affiliation: Department of Thyroid Gland and Breast Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Thyroid Gland and Breast Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Xi'an Health Management Service Center, Xi'an 710032, Shaanxi Province, PR China.
authors.forename: Chang-You
authors.initials: CY
authors.lastname: Yan
authors.affiliation: Department of Thyroid Gland and Breast Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, PR China. Electronic address: lingrui0105@163.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Ling
authors.affiliation: Department of Thyroid Gland and Breast Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, PR China. Electronic address: yunjun@fmmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Yun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D043823:Taxoids; D000077143:Docetaxel
keywords: Breast cancer; HIF-1α; Hyperinsulinemia; Oxidative stress; Type 2 diabetes mellitus