Thursday, April 3, 2025
4/3/2025
Non-canonical roles of Mitotic Arrest Deficient 1 (Mad1) in tumor promotion - Breast cancer is the most commonly diagnosed malignancy in women worldwide. Mitotic Arrest Deficient 1 (Mad1) is commonly upregulated in breast cancer where it serves as a marker of poor prognosis, and upregulation of Mad1 is sufficient for tumorigenesis in orthotopic breast cancer models. Mad1 was identified and characterized for its function in mitosis, where it serves to prevent chromosome missegregation/chromosomal instability (CIN). CIN has been implicated in promoting both primary and metastatic tumors. However, Mad1 is expressed throughout interphase and we have recently shown that a non-canonical interphase function of Mad1 in destabilizing the p53 tumor suppressor is critical for Mad1 upregulation to promote orthotopic mammary tumor growth. Additionally, we identified a previously unrecognized pool of Mad1 that localizes to the Golgi apparatus. At the Golgi, Mad1 performs another non-canonical function in the maturation and secretion of newly synthesized α5 integrin, a critical metastasis promoter and marker of poor prognosis. Thus, Mad1 upregulation results in three tumor- and metastasis-promoting phenotypes: CIN, p53 destabilization and α5 integrin secretion. Aim 1 will determine which functions of Mad1 upregulation are necessary and sufficient for tumor promotion using separation of function mutants, competition experiments, specific inhibitors, and novel CRISPR/Cas9 edited mouse models. Aim 2 will define the mechanisms by which Mad1 functions in the secretion of newly synthesized α5 integrin, which will provide novel opportunities to inhibit α5 integrin activity in promoting metastasis. Together, the proposed experiments will identify the mechanistic basis of the tumor promoting activity of Mad1 and define the α5 integrin biosynthetic trafficking pathway, which will expand our fundamental understanding of breast cancer and reveal novel therapeutic targets.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).