Presenter: Amanda Henning
Amanda N. Henning, Adeline L. Veillet, Bart M. Smits, Jill D. Haag, and Michael N. Gould University of Wisconsin - Madison, McArdle Laboratory for Cancer Research
Identifying genetic factors that contribute to breast cancer risk is critical for both risk assessment and the development of new therapeutics. It is thought that many such risk factors are high-frequency, low-penetrant alleles, which are largely found to reside in non-coding regions, making functional studies difficult. Using a rat model of breast cancer, our lab has identified many such loci, including Mammary Carcinoma Susceptibility 5c, (Mcs5c), which was found to decrease tumor multiplicity by 55% in congenic rats possessing the resistant allele. The Mcs5c locus spans 170kb on rat chromosome 5 and lies in a 1Mb gene desert. Mammary gland transplant experiments found that Mcs5c acts in a mammary cell autonomous manner. Expression analysis on surrounding genes indentified PAPPA as a likely target of Mcs5c action. Expression of PAPPA is reduced by 30-50% in the mammary gland of resistant rats at 6, 7, and 9 weeks of age. This represents a critical time during mammary gland development when animals are most susceptible to cancer initiation. Mcs5c may mediate changes in gene expression through an enhancer element that interacts with its target gene via chromatin folding. Chromosome conformation capture was used to detect such folding, and found that Mcs5c interacts with PAPPA at its proximal promoter in 12 week samples. PAPPA is an important regulator of IGF bioavailability and its reduced expression in resistant animals is consistent with a role in tumor reduction. At this time, it appears that Mcs5c mediates tumor resistance via modification of PAPPA expression in the mammary gland.