Mechanisms Underlying the Breast Cancer Susceptibility Locus Mcs5a

摘要

For low-penetrance breast cancer risk alleles it is currently unknown how they lead to predisposition. Here, we study the Mcs5a locus that is associated with breast cancer risk in rats and humans. In our rat model we show that the presence of the resistant genotype of two components of the locus (Mcs5a1, Mcs5a2) down regulates the expression of the Fbxo10 gene in the T cells and that this reduced expression is associated with reduced mammary tumor multiplicity. We show that genetic elements in Mcs5a1 and Mcs5a2 are physically close to each other in the nuclear space. The spatial organization of the locus in primary T cells is conserved between rat and human. We demonstrate that the function of the non-coding Mcs5a locus likely is repressive gene regulation. We present a model that begins to explain how the Fbxo10 gene could be regulated in T cells.