Long-Chain Fatty Acid Analogues Suppress Breast Tumorigenesis and Progression

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 b-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 carbohydraterestricted 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. Cancer Res; 74(23); 6991-7002. Ó2014 AACR.

Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

“…The striking feature of the work done to date in a number of model systems using different dietary interventions is that alterations in metabolism have a far reaching effect on tumor cells, tumors and the tumor microenvironment. Studies have shown reductions in growth rate as one might expect however, there are also changes in the formation of reactive oxygen species and oxidative stress (Stafford et al, 2010; Milder and Patel, 2012; Allen et al, 2013), angiogeneisis (Zhou et al, 2007; Jiang and Wang, 2013; Woolf et al, 2015), hypoxia (Maurer et al, 2011; Poff et al, 2015; Woolf et al, 2015), inflammation and peri-tumoral edema (Mavropoulos et al, 2009; Woolf et al, 2015), metastasis and invasion (Gluschnaider et al, 2014; Lv et al, 2014; Hao et al, 2015; Poff et al, 2015) and the expression of various transcriptional and post-transcriptional modulators such as NF-κB (Woolf et al, 2015) and microRNAs (Pazmandi et al, 2015). …”

The Ketogenic Diet as an Adjuvant Therapy for Brain Tumors and Other Cancers

“…For example, Gluschnaider et al used the MMTVPyMT oncomouse model to demonstrate that a KD suppressed breast tumor growth (Gluschnaider et al 2014). Likewise, Allen et al showed that the KD enhanced radiation and chemotherapy responses in a mouse lung xenograft model by increasing oxidative stress in both NCI-H292 and A549 lung xenograft models (Allen et al 2013).…”

Critical Dietary Factors in Cancer Chemoprevention

“…For example, Gluschnaider et al used the MMTV-PyMT oncomouse model to demonstrate that a KD suppressed breast tumor growth (Gluschnaider et al 2014). For example, Gluschnaider et al used the MMTV-PyMT oncomouse model to demonstrate that a KD suppressed breast tumor growth (Gluschnaider et al 2014).…”