This proposal is based on our preliminary studies in a chemically-induced non-obese rat model for breast cancer in which consumption of cooked cannellini bean, a distinct variety of common bean (Phaseolus vulgaris L.), reduced breast cancer incidence by 70%, tumor multiplicity by 3-fold, and tumor mass by 5-fold. Overall hypothesis Cannellini bean, common in Mediterranean diets, exerts breast cancer inhibitory activity by systemic effects on obesity associated insulin resistance, chronic inflammation, and peripheral aromatization and directly via effects on cell signaling networks that affect carcinogenesis.
Specific Aims The proposed experiments will use either 1) chemically induced, obesity sensitive or resistant rat models for breast cancer with well characterized differences in HR receptor status and HER2/Neu expression, or 2) a mouse model in which mTOR-related signaling is deregulated in mammary epithelial cells.
Aim 1. Hypothesis: Cannellini bean feeding attenuates deregulated mTOR signaling The rationale for this aim is that cannellini bean exerts effects systemically by reducing signaling via the insulin/IGF-1 pathway and intracellularly by activating LKB1/AMPK/raptor and SIRT1 signaling nodes and induces TSC1/2 repressor activity which counteract the effects of mTOR de-regulation. Dissection of the mechanisms of mTOR network regulation will focus on site specific phosphorylations of TSC2, PRAS40, Akt, LKB1, AMPK and raptor as well as assessing mTOR downstream targets S6kinase, 4E-BP1, and FOXO3a.
Aim 2. Hypothesis: Cannellini bean feeding inhibits obesity-associated peripheral aromatization. The underlying rationale is that feeding cannellini bean improves insulin sensitivity, decreases chronic inflammation, and activates the LKB1/AMPK axis, thereby suppressing peripheral aromatization and tumor development.
Aim 3. Hypothesis: Cannellini bean feeding inhibits de novo intra-tumoral lipid synthesis De novo lipid synthesis is a universal characteristic in breast cancer and inhibition of lipid synthesis would be expected to delay tumor occurrence and reduce tumor size, consistent with observed effects of cannellini on mammary carcinogenesis. Work will concentrate on identifying alterations in key regulatory nodes in lipid synthesis associated with rapid tumor growth. These analyses will be complemented by assessment for membrane phospholipid constituents linked to tumor aggressiveness. Hypothesized origins of effects on lipid metabolism include down regulation of mTOR-related signaling and suppression of chronic inflammation.
As a staple food crop, common bean is consistently eaten in large amounts on a daily basis as a primary source of proteins and micronutrients in many populations around the world. Unfortunately, in the United States, where the prevalence of breast cancer is among the highest in the world, over 60% of Americans report that they consume no common beans on a daily basis and per capita intake is less than 10g/day. Given our pre-clinical findings, together with results of prospective population-based studies indicating a relationship between bean consumption and lower rates of breast cancer, there is a remarkable and unappreciated promise to reduce breast cancer risk and promote long term survival following treatment via increasing bean consumption.