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Identifying molecular features that distinguish fluvastatin-sensitive breast tumor cells

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Abstract

Statins, routinely used to treat hypercholesterolemia, selectively induce apoptosis in some tumor cells by inhibiting the mevalonate pathway. Recent clinical studies suggest that a subset of breast tumors is particularly susceptible to lipophilic statins, such as fluvastatin. To quickly advance statins as effective anticancer agents for breast cancer treatment, it is critical to identify the molecular features defining this sensitive subset. We have therefore characterized fluvastatin sensitivity by MTT assay in a panel of 19 breast cell lines that reflect the molecular diversity of breast cancer, and have evaluated the association of sensitivity with several clinicopathological and molecular features. A wide range of fluvastatin sensitivity was observed across breast tumor cell lines, with fluvastatin triggering cell death in a subset of sensitive cell lines. Fluvastatin sensitivity was associated with an estrogen receptor alpha (ERα)-negative, basal-like tumor subtype, features that can be scored with routine and/or strong preclinical diagnostics. To ascertain additional candidate sensitivity-associated molecular features, we mined publicly available gene expression datasets, identifying genes encoding regulators of mevalonate production, non-sterol lipid homeostasis, and global cellular metabolism, including the oncogene MYC. Further exploration of this data allowed us to generate a 10-gene mRNA abundance signature predictive of fluvastatin sensitivity, which showed preliminary validation in an independent set of breast tumor cell lines. Here, we have therefore identified several candidate predictors of sensitivity to fluvastatin treatment in breast cancer, which warrant further preclinical and clinical evaluation.

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Acknowledgments

This study was conducted with financial support from the Canada Research Chairs Program (LZP), the Ontario Institute for Cancer Research through funding provided by the Province of Ontario (LZP, PCB), the Canadian Breast Cancer Foundation, Ontario Region (LZP, CAG, ARW), and the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the Ontario Ministry of Health and Long Term Care. We also thank members of the Penn and Boutros Labs for critical review of this manuscript and all providers of cell lines for thoughtful discussions and technical advice, especially Dr. Mona Gauthier, Bernard Martin, Dr. Benjamin Neel and Dr. Richard Marcotte. We thank Priscilla DeLuca for administrative support.

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The authors declare no potential competing financial interests.

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Correspondence to Linda Z. Penn.

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Goard, C.A., Chan-Seng-Yue, M., Mullen, P.J. et al. Identifying molecular features that distinguish fluvastatin-sensitive breast tumor cells. Breast Cancer Res Treat 143, 301–312 (2014). https://doi.org/10.1007/s10549-013-2800-y

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