Insulin receptor loss impairs mammary tumorigenesis in mice
Lauren Podmore,
Yekaterina Poloz,
Catherine Iorio,
Samar Mouaaz,
Kevin Nixon,
Petr Smirnov,
Brianna McDonnell,
Sonya Lam,
Bowen Zhang,
Pirashaanthy Tharmapalan,
Soumili Sarkar,
Foram Vyas,
Marguerite Ennis,
Ryan Dowling,
Vuk Stambolic
Affiliations
Lauren Podmore
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Yekaterina Poloz
Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Catherine Iorio
Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Samar Mouaaz
Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Kevin Nixon
Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Petr Smirnov
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Brianna McDonnell
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Sonya Lam
Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Bowen Zhang
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Pirashaanthy Tharmapalan
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Soumili Sarkar
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Foram Vyas
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Marguerite Ennis
Applied Statistician, Markham, ON L3R 6H9, Canada
Ryan Dowling
Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada
Vuk Stambolic
Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, Canada; Corresponding author
Summary: Breast cancer (BC) prognosis and outcome are adversely affected by obesity. Hyperinsulinemia, common in the obese state, is associated with higher risk of death and recurrence in BC. Up to 80% of BCs overexpress the insulin receptor (INSR), which correlates with worse prognosis. INSR’s role in mammary tumorigenesis was tested by generating MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC mouse models, respectively, with coordinate mammary epithelium-restricted deletion of INSR. In both models, deletion of either one or both copies of INSR leads to a marked delay in tumor onset and burden. Longitudinal phenotypic characterization of mouse tumors and cells reveals that INSR deletion affects tumor initiation, not progression and metastasis. INSR upholds a bioenergetic phenotype in non-transformed mammary epithelial cells, independent of its kinase activity. Similarity of phenotypes elicited by deletion of one or both copies of INSR suggest a dose-dependent threshold for INSR impact on mammary tumorigenesis.
