The role of UbcH7 in male breast cancer

Abstract While breast cancer is one of the most common cancers in women in the U.S., it is extremely rare in men, accounting for less than 1% of all breast cancer cases. Although there are several factors that may increase the risk of developing male breast cancer, the fundamental disease-defining molecular pathway of this rare cancer remains unknown. As a result, male breast cancer has

been considered similar to female breast cancer even though accumulating evidence indicates that breast cancers in men may be genetically and epigenetically distinct. Unfortunately, unlike female breast cancer, the lack of model systems hinders the investigation of male breast cancer. The ubiquitin/proteasome system (UPS) plays a critical role in the regulation of protein quality

control through protein degradation. Dysregulation of the UPS has been implicated in several diseases, including neurodegenerative disorders and cancer. The UPS is composed of 3 critical enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). While E3 ligases are often found to be dysregulated in cancer, the

pathophysiological significance of the E2 ubiquitin-conjugating enzymes remains elusive. UbcH7 (also known as Ube2l3) is one of the E2 enzymes ubiquitously expressed in various tissues and organs. Our lab has recently discovered that UbcH7 heterozygosity (UbcH7+/) significantly promotes the incidence of male breast cancer in MMTV-Neu mice, a mouse model of HER2+

human breast cancer. Importantly, the loss of one copy of UbcH7 does not have any effects in female breast cancer. To the best of our knowledge, this is the first transgenic mouse model that promotes breast cancer only in males. Based on these results, we hypothesize that UbcH7 plays a unique role in the prevention of male breast cancer by promoting the degradation of an

oncoprotein which only influences mammary tumorigenesis in males. The ultimate goal of this project is to identify the “male-specific oncoprotein” in breast cancer. Towards this goal, we will first investigate the pathophysiological conditions of UbcH7+/- male mice, especially focusing on mammary gland development (Aim 1). We will then perform in vivo 2H2O-labeling and mass

spectrometry-based proteomics to identify the substrates of UbcH7 in male mammary glands (Aim 2). Furthermore, we also plan to conduct RNA-seq to identify an altered signaling pathway(s) in UbcH7+/- mammary glands. Despite numerous studies on breast cancer, the mechanisms that regulate male breast cancer remain poorly understood. We expect that our studies will place

UbcH7 as a novel predisposition gene for the development of male breast cancer, serving as a breakthrough that will open up a new direction of research in this field.