Therapeutic Targeting of SET1B/Compass Pathway in Treating Triple-Negative Breast Cancer

Mutations and translocations within COMPASS (Complex Proteins Associated with Set1) family of histone lysine methyltransferases are associated with a large number of human diseases including cancer. We report that SET1B/COMPASS is overexpressed in human breast cancer and that COMPASS overexpression significantly correlates with ER-negative patient survival. We have also demonstrated that the depletion of SET1B selectively inhibits multiple triple negative breast cancer (TNBC) cell survival in vitro and in vivo but does not affect ER-positive or normal epithelia cell growth. Surprisingly, in TNBC, SET1B/COMPASS regulates a specific gene expression profile without affecting histone H3 methylation. We further identified that SET1B as the only cytoplasmic form of COMPASS, with BOD1 as its unique cytoplasmic subunit interacting with the N-terminus of SET1B. Furthermore, we demonstrated that that loss of SET1B or the SET1B/BOD1 interaction induces activation of ADIPOR1 signaling pathway, which is inactivated in both obesity and during TNBC development. Finally, we found that a small molecular agonist for the SET1B/COMPASS target, the Adiponectin receptor 1, can dramatically inhibit TNBC growth in vitro and in vivo. Collectively, our results elucidate a new function for SET1B/COMPASS in the cytoplasm, which can be harnessed for a therapeutic strategy regulating signaling in human breast cancer.