Growth and development of the mammary glands occurs under the influence of circulating hormones and paracrine cues closely aligned with reproductive development. Development of the mammary glands during puberty is estrogen-dependent, whereby removal of the ovaries suspends all mammary growth. In parallel, a growing body of evidence suggests that diet can promote growth of the mammary glands, which may increase breast cancer risk. We have made the important finding that trans-10, cis- 12 conjugated linoleic acid (10, 12 CLA), a specific dietary fat, can stimulate the mammary glands to grow in the absence of estrogen and independent of the estrogen receptor. Similarly, we demonstrated that 10, 12 CLA stimulates tumorigenesis in a transgenic mouse model of human breast cancer. In parallel, dietary 10, 12 CLA induces whole-body metabolic changes including fat accumulation in the liver, inflammation, elevated insulin levels, and insulin resistance. Importantly, our data indicate that signaling via growth factor receptors may be responsible for mediating mammary growth induced by 10,12 CLA. Intriguingly, these same pathways have been implicated in in aggressive, estrogen-independent breast cancers. I propose to test the hypothesis that specific growth factor signaling networks are responsible for estrogen-independent mammary growth stimulated by this dietary fat. I will first establish the temporal response of the mammary glands to dietary 10, 12 CLA. Next, I will examine the protein and mRNA expression levels of specific growth factor signaling molecules. Lastly, I will use cutting edge RNA-sequencing technology to probe downstream signaling networks that may be over-represented in the mammary glands of ovariectomized mice fed 10,12 CLA. These studies stand to identify new targets for the treatment of estrogen-independent breast cancers and to highlight potential mechanisms of how diet might promote mammary tumorigenesis.
This research project seeks to resolve the fundamental mechanisms behind estrogen-independent mammary growth induced by a dietary fat, trans-10, cis-12 conjugated linoleic acid (10,12 CLA). Consumption of 10,12 CLA leads to many complex phenotypic changes including reduced adiposity, increased lipid accumulation in the liver, increased inflammation, elevated serum insulin levels and insulin resistance in addition to its profound effects on the mammary glands. Notably, many of the phenotypic changes induced by dietary 10,12 CLA closely recapitulate aspects of the metabolic syndrome. This unique model affords us a powerful system in which to study the effects of diet, metabolic dysregulation, and aberrant growth factor signaling on estrogen-independent mammary growth, and holds important translational implications for aggressive, hormone-independent breast cancers.