Insulin receptor loss impairs mammary tumorigenesis in mice
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723012639 |
| _version_ | 1797448098070396928 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lauren Podmore |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T14:05:28Z |
| format | Article |
| id | doaj.art-0a98286f0bdb4289aa404e39db449838 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-09T14:05:28Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-0a98286f0bdb4289aa404e39db4498382023-11-30T05:06:36ZengElsevierCell Reports2211-12472023-11-014211113251Insulin receptor loss impairs mammary tumorigenesis in miceLauren Podmore0Yekaterina Poloz1Catherine Iorio2Samar Mouaaz3Kevin Nixon4Petr Smirnov5Brianna McDonnell6Sonya Lam7Bowen Zhang8Pirashaanthy Tharmapalan9Soumili Sarkar10Foram Vyas11Marguerite Ennis12Ryan Dowling13Vuk Stambolic14Department of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaPrincess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaPrincess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaPrincess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaPrincess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaDepartment of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaDepartment of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaPrincess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaDepartment of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaDepartment of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaDepartment of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaDepartment of Medical Biophysics, University of Toronto, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaApplied Statistician, Markham, ON L3R 6H9, CanadaPrincess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON M5G 1L7, CanadaDepartment 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723012639CP: Cancer |
| spellingShingle | 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 Insulin receptor loss impairs mammary tumorigenesis in mice Cell Reports CP: Cancer |
| title | Insulin receptor loss impairs mammary tumorigenesis in mice |
| title_full | Insulin receptor loss impairs mammary tumorigenesis in mice |
| title_fullStr | Insulin receptor loss impairs mammary tumorigenesis in mice |
| title_full_unstemmed | Insulin receptor loss impairs mammary tumorigenesis in mice |
| title_short | Insulin receptor loss impairs mammary tumorigenesis in mice |
| title_sort | insulin receptor loss impairs mammary tumorigenesis in mice |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723012639 |
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