Prolactin (PRL) involvement in breast cancer progression is increasingly recognized, yet its actions are poorly understood. Clinically, circulating PRL levels and density of the extracellular matrix (ECM) alone are significant risk factors for breast cancer. In mouse models, PRL promotes mammary carcinomas that resemble aggressive luminal breast cancers in women, and increased collagen density promotes tumor metastasis and progression. Although recent studies are illuminating the contributions of the ECM to the physiological actions of prolactin, little is known about the functional relationship between ECM density and PRL signaling in breast cancer. Here, our goal is to elucidate the interaction between collagen density and PRL signaling in breast cancer progression. In this revised application, I will test the hypothesis that PRL and stiff collagen matrices interact to promote mammary tumorigenesis and progression via association of PRL receptors with beta-integrins and lipid rafts, driving tumorigenic PRL actions through the FAK-SFK-ERK1/2 pathway. Specifically, I will determine the molecular mechanisms that control the interactions between ECM density and PRL signaling in breast cancer cells in a defined in vitro system (Aim 1), and examine the interplay between collagen density and PRL signaling in the development and progression of luminal mammary tumors in vivo, using a PRL transgenic mouse with humanized PRL expression and a genetically modified mouse that mimics the elevated collagen density observed in a subset of women (Aim 2). Achievement of these aims will lead to a more complete understanding of the complex interactions between the ECM and prolactin in breast cancer. This will allow for an informed approach for the development of novel therapeutics that uncouple elevated matrix density from pro-tumorigenic signaling pathways. Achieving the scientific goals of this proposal is only the first step in developing into an independent academic research scientist. Taking advantage of the outstanding facilities, faculty and training opportunities at UW-Madison, as well as the mentorship of my sponsor, I also will grow as an independent investigator in the areas of critical thinking, communication, mentoring and responsible conduct of research. This fellowship will aid in my development as a cancer biologist so that I may establish my own research group to discover new therapeutic and preventative approaches to cancer and train future scientist in cancer and cellular biology.
Two major risk factors for breast cancer in women are prolactin exposure and breast density. By examining the mechanism and functional outcome of the interaction of elevated collagen density and prolactin in the progression of breast cancer, the results of the experiments proposed in this application will lead to an increased understanding of this important relationship and reveal avenues for the design of novel therapeutics.
|Barcus, Craig E; Keely, Patricia J; Eliceiri, Kevin W et al. (2016) Prolactin signaling through focal adhesion complexes is amplified by stiff extracellular matrices in breast cancer cells. Oncotarget 7:48093-48106|
|Barcus, Craig E; Holt, Elizabeth C; Keely, Patricia J et al. (2015) Dense collagen-I matrices enhance pro-tumorigenic estrogen-prolactin crosstalk in MCF-7 and T47D breast cancer cells. PLoS One 10:e0116891|