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Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model

Oncogene volume 32, pages 961–967 (2013)Cite this article

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Abstract

Dyslipidemia has been associated with an increased risk for developing cancer. However, the implicated mechanisms are largely unknown. To explore the role of dyslipidemia in breast cancer growth and metastasis, we used the apolipoprotein E (ApoE) knockout mice (ApoE−/−), which exhibit marked dyslipidemia, with elevated circulating cholesterol and triglyceride levels in the setting of normal glucose homeostasis and insulin sensitivity. Non-metastatic Met-1 and metastatic Mvt-1 mammary cancer cells derived from MMTV-PyVmT/FVB-N transgenic mice and c-Myc/vegf tumor explants respectively, were injected into the mammary fat pad of ApoE−/− and wild-type (WT) females consuming a high-fat/high-cholesterol diet and tumor growth was evaluated. ApoE−/− mice exhibited increased tumor growth and displayed a greater number of spontaneous metastases to the lungs. Furthermore, intravenous injection of Mvt-1 cells resulted in a greater number of pulmonary metastases in the lungs of ApoE−/− mice compared with WT controls. To unravel the molecular mechanism involved in enhanced tumor growth in ApoE−/− mice, we studied the response of Mvt-1 cells to cholesterol in vitro. We found that cholesterol increased AktS473 phosphorylation in Mvt-1 cells as well as cellular proliferation, whereas cholesterol depletion in the cell membrane abrogated AktS473 phosphorylation induced by exogenously added cholesterol. Furthermore, in vivo administration of BKM120, a small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), alleviated dyslipidemia-induced tumor growth and metastasis in Mvt-1 model with a concomitant decrease in PI3K/Akt signaling. Collectively, we suggest that the hypercholesterolemic milieu in the ApoE−/− mice is a favorable setting for mammary tumor growth and metastasis.

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Acknowledgements

This work was supported by ADA mentor-based postdoctoral fellowship award 7-08-MN-33 and National Cancer Institute Grant RO1CA128799, both to DLR. We thank Novartis for providing us with BKM120 compound. In addition, partial support was from the Israel Cancer Association to DLR.

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Authors and Affiliations

  1. Division of Endocrinology, The Samuel Bronfman Department of Medicine, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY, USA

    N Alikhani, R D Ferguson, R Novosyadlyy, E J Gallagher, S Yakar & D LeRoith

  2. Diabetes and Metabolism Clinical Research Center of Excellence, Clinical Research Institute at Rambam (CRIR), Haifa, Israel

    E J Scheinman & D LeRoith

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  1. N Alikhani
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  2. R D Ferguson
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Correspondence to D LeRoith.

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Alikhani, N., Ferguson, R., Novosyadlyy, R. et al. Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model. Oncogene 32, 961–967 (2013). https://doi.org/10.1038/onc.2012.113

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