Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes

Ruslan Novosyadlyy, Danielle E. Lann, Archana Vijayakumar, Anne Rowzee, Deborah A. Lazzarino, Yvonne Fierz, Joan M. Carboni, Marco M. Gottardis, Patricia A. Pennisi, Alfredo A. Molinolo, Naamit Kurshan, Wilson Mejia, Stefania Santopietro, Shoshana Yakar, Teresa L. Wood, Derek LeRoith

Research output: Contribution to journalArticle

Abstract

Epidemiologic studies suggest that type 2 diabetes (T2D) increases breast cancer risk and mortality, but there is limited experimental evidence supporting this association. Moreover, there has not been any definition of a pathophysiological pathway that diabetes may use to promote tumorigenesis. In the present study, we used the MKR mouse model of T2D to investigate molecular mechanisms that link T2D to breast cancer development and progression. MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/ IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. Tumor-promoting effects of T2D in the models were reversed by pharmacological blockade of IR/IGF-IR signaling by the small-molecule tyrosine kinase inhibitor BMS-536924. Our findings offer compelling experimental evidence that T2D accelerates mammary gland development and carcinogenesis,and that the IR and/or the IGF-IR are major mediators of these effects.

Original languageEnglish (US)
Pages (from-to)741-751
Number of pages11
JournalCancer Research
Volume70
Issue number2
DOIs
StatePublished - Jan 15 2010

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IGF Type 1 Receptor
Type 2 Diabetes Mellitus
Insulin Receptor
Insulin
Breast Neoplasms
Phosphorylation
Human Mammary Glands
Carcinogenesis
Breast
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Transgenes
Protein-Tyrosine Kinases
Epidemiologic Studies
Skeletal Muscle
Phosphotransferases
Pharmacology
Glucose
Mortality
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Novosyadlyy, R., Lann, D. E., Vijayakumar, A., Rowzee, A., Lazzarino, D. A., Fierz, Y., ... LeRoith, D. (2010). Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Research, 70(2), 741-751. https://doi.org/10.1158/0008-5472.CAN-09-2141

Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. / Novosyadlyy, Ruslan; Lann, Danielle E.; Vijayakumar, Archana; Rowzee, Anne; Lazzarino, Deborah A.; Fierz, Yvonne; Carboni, Joan M.; Gottardis, Marco M.; Pennisi, Patricia A.; Molinolo, Alfredo A.; Kurshan, Naamit; Mejia, Wilson; Santopietro, Stefania; Yakar, Shoshana; Wood, Teresa L.; LeRoith, Derek.

In: Cancer Research, Vol. 70, No. 2, 15.01.2010, p. 741-751.

Research output: Contribution to journalArticle

Novosyadlyy, R, Lann, DE, Vijayakumar, A, Rowzee, A, Lazzarino, DA, Fierz, Y, Carboni, JM, Gottardis, MM, Pennisi, PA, Molinolo, AA, Kurshan, N, Mejia, W, Santopietro, S, Yakar, S, Wood, TL & LeRoith, D 2010, 'Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes', Cancer Research, vol. 70, no. 2, pp. 741-751. https://doi.org/10.1158/0008-5472.CAN-09-2141
Novosyadlyy, Ruslan ; Lann, Danielle E. ; Vijayakumar, Archana ; Rowzee, Anne ; Lazzarino, Deborah A. ; Fierz, Yvonne ; Carboni, Joan M. ; Gottardis, Marco M. ; Pennisi, Patricia A. ; Molinolo, Alfredo A. ; Kurshan, Naamit ; Mejia, Wilson ; Santopietro, Stefania ; Yakar, Shoshana ; Wood, Teresa L. ; LeRoith, Derek. / Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. In: Cancer Research. 2010 ; Vol. 70, No. 2. pp. 741-751.
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