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Evidence for a tumor promoting effect of high-fat diet independent of insulin resistance in HER2/Neu mammary carcinogenesis

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Abstract

The mechanism of the association between breast cancer and obesity remains unknown. To investigate this mice over-expressing HER2/Neu in the mammary gland (MMTV-HER2/Neu) were fed either a high-fat diet (45% of calories) (HFD) or low-fat diet (10%) (LFD) from 4 weeks of age and followed for up to 1 year, or sacrificed when a mammary tumor reached 1.5 cm. There was a small but significant increase in body weight on HFD (P < 0.05) and the HFD mice displayed a greater fat mass determined by MRI (P < 0.01). Mild glucose intolerance was observed from 3 months of age on HFD, but insulin levels were not elevated. While the time of onset of a first tumor and tumor growth rates were not altered, mice on HFD had an earlier onset of a second tumor and a twofold greater incidence (LFD 25%, HFD 54%) and a greater absolute number of multiple tumors (tumors/mouse, LFD 1.5 ± 0.25 vs. HFD 2.7 ± 0.23, P < 0.01). Consistent with a lack of hyperinsulinemia, immunoblotting of skeletal muscle lysates from mice injected with insulin showed no insulin resistance determined by the phosphorylation of Akt/PKB. Similarly, there was no difference in basal or maximum insulin-stimulated phosphorylation of IRS-1/2, Akt/PKB, or p70 S6K in tumor cell lysates from HFD and LFD groups. Immunohistochemistry revealed no difference in tumor tissue staining for the proliferative marker, Ki67, between diets. These data indicate that HFD, in the absence of significant insulin resistance, mediates a tumor promoting, but not a tumor growth effect in this model of mammary carcinogenesis.

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Acknowledgments

This work was funded by a Canadian Breast Cancer Research Alliance and Canadian Institutes of Health Research Translational Acceleration Research Grant (TAG) # 016512 to IGF. SK was supported by the TAG and in part by the Marvelle Koffler Breast Cancer Research Centre, Mount Sinai Hospital.

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Authors and Affiliations

  1. Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada

    Sarah Khalid, Pamela J. Goodwin & I. George Fantus

  2. Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network and Banting and Best Diabetes Centre, Toronto, ON, Canada

    Sarah Khalid, David Hwang, Yael Babichev, Rani Kolli, Svetlana Altamentova, Shlomit Koren & I. George Fantus

  3. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    Sarah Khalid, David Hwang, Yael Babichev, Rani Kolli, Svetlana Altamentova, Shlomit Koren, Pamela J. Goodwin & I. George Fantus

  4. Marvelle Koffler Breast Center, Mount Sinai Hospital, Toronto, ON, Canada

    Marguerite Ennis

  5. Department of Oncology, Cancer Prevention Research Unit, McGill University, Montreal, QC, Canada

    Michael Pollak

  6. Department of Biochemistry, McGill University, Montreal, QC, Canada

    Nahum Sonenberg

  7. Department of Medicine, Mount Sinai Hospital, 60 Murray Street, Rm. 5-028, Toronto, ON, M5T 3L9, Canada

    I. George Fantus

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  1. Sarah Khalid
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Correspondence to I. George Fantus.

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Khalid, S., Hwang, D., Babichev, Y. et al. Evidence for a tumor promoting effect of high-fat diet independent of insulin resistance in HER2/Neu mammary carcinogenesis. Breast Cancer Res Treat 122, 647–659 (2010). https://doi.org/10.1007/s10549-009-0586-8

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