Mechanisms linking Cancer Disparities and Metabolic Status

More African American (AA) women die from breast cancer (BrCa) compared to women from other ethnic groups. Both social (socioeconomic, diet) and biological (gene expression, polymorphisms) factors impact BrCa disparities. BrCa disparities in AA women are further exacerbated by high rate of obesity in this population, given that obesity is a risk factor for postmenopausal BrCa and is linked with inflammation, drug resistance and poor prognosis. Diets high in sugars and certain fats (most common causes of obesity) also lead to increased ingestion and accrual of dietary environmental toxicants, adding further cancer risk. While correlations of these phenomena have been observed, the underlying mechanisms remain elusive. We recently reported Lipolysis Stimulated Lipoprotein Receptor (LSR) as a putative link between BrCa progression, obesity, high fat diet and BrCa disparities. LSR is over-expressed in BrCa, traffics to the nucleus, binds to DNA, and, importantly, nuclear LSR is associated with poor prognosis49. LSR also modulates tumorigenesis, EMT, drug resistance and cancer stem cell phenotype1, TCGA data analysis from 1,218 primary tumors show that LSR is more highly expressed in AA vs. White BrCa (P=3.1e-11) and overexpression is correlated with poor survival49. Our pilot data demonstrate that high levels of LSR are significantly correlated with basal-like and luminal BrCa49, and murine models of diet-induced obesity. We also show that LSR mediates lipid endocytosis in BrCa cells shifting cellular bioenergetics. LSR mediates hepatic lipid endocytosis and is deregulated by dietary toxicants, providing new insight into mechanisms underlying the involvement of pollutants in the disruption of lipid homeostasis, potentially contributing to dyslipidemia, obesity and its associated inflammation. The tissue specific effects of toxicant-driven LSR deregulation in breast tissue and BrCa remains to be determined. We hypothesize that higher LSR levels modulate cellular bioenergetics and inflammatory mediators that may alter transcriptome regulation and cancer cell signaling, leading to an aggressive BrCa phenotype, disparities and poor prognosis.