Abstract

Obesity and type 2 diabetes (T2D) are associated with increased breast cancer incidence and mortality, whereas carbohydrate-restricted ketogenic diets ameliorate T2D and suppress breast cancer. These observations suggest an inherent efficacy of nonesterified long-chain fatty acids (LCFA) in suppressing T2D and breast tumorigenesis. In this study, we investigated novel antidiabetic MEDICA analogues consisting of methyl-substituted LCFA that are neither β-oxidized nor esterified to generate lipids, prompting interest in their potential efficacy as antitumor agents in the context of breast cancer. In the MMTV-PyMT oncomouse model of breast cancer, in which we confirmed that tumor growth could be suppressed by a carbohydrate-restricted ketogenic diet, MEDICA treatment suppressed tumor growth, and lung metastasis, promoting a differentiated phenotype while suppressing mesenchymal markers. In human breast cancer cells, MEDICA treatment attenuated signaling through the STAT3 and c-Src transduction pathways. Mechanistic investigations suggested that MEDICA suppressed c-Src-transforming activity by elevating reactive oxygen species production, resulting in c-Src oxidation and oligomerization. Our findings suggest that MEDICA analogues may offer therapeutic potential in breast cancer and overcome the poor compliance of patients to dietary carbohydrate restriction.

Highlights

  • Breast cancer is the most common invasive cancer in women

  • Mammary carcinoma develops in stages consisting of early hyperplastic ductal lesions that progress to adenoma, carcinoma in situ and lung metastasis

  • Association of the Polyoma Middle T antigen (PyMT)/PP2A/c-Src complex with the plasma membrane is required for its transforming activity [4], implying that the complex may be visualized as an oncogenic receptor tyrosine kinase (RTK), with c-Src acting as its obligatory tyrosine kinase

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Summary

Introduction

Breast cancer is the most common invasive cancer in women. Mammary carcinoma develops in stages consisting of early hyperplastic ductal lesions that progress to adenoma, carcinoma in situ and lung metastasis. Mice expressing the Polyoma Middle T antigen (PyMT) driven by the mammary MMTV promoter (MMTV-PyMT) are widely used as the animal model for human breast cancer To human tumors, mammary carcinoma in MMTV-PyMT mice develops in stages consisting of early hyperplastic lesions located on end buds of collecting ducts, which progress to adenoma/mammary intraepithelial neoplasia, carcinoma in situ and lung metastasis [2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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