ORY-1001, a KDM1A inhibitor, inhibits proliferation, and promotes apoptosis of triple negative breast cancer cells by inactivating androgen receptor.

Breast cancer (BC), which is widely considered as the most common cancer in women around the world, evokes ~1.7 million new BC cases and 522,000 BC-related deaths each year. Triple negative breast cancer (TNBC) is clinically confirmed as one of the most aggressive subtypes of BC. ORY-1001, a clinically used lysine specific demethylase 1 (LSD1/KDM1A) inhibitor, was investigated herein to confirm its role in the progression of TNBC and reveal the potential mechanism. After treatment with ORY-1001 in MDA-MB-231 and BT549 cells, the cell proliferation and apoptosis were respectively measured by CCK-8 and TUNEL assays. The expression of proliferation- and apoptosis-associated proteins was tested by means of western blot analysis. Then, R1881, an androgen receptor (AR) agonist, was used to evaluate whether the effects of ORY-1001 on proliferation and apoptosis of TNBC cells was mediated by regulating AR. Results indicated that ORY-1001 treatment restrained the proliferation while enhanced the apoptosis of BC cells, accompanied by the change of proliferation- and apoptosis-related proteins expression. Furthermore, ORY-1001 reduced the level of AR in BC cells. After the activation of AR by R1881, the decreased proliferation and enhanced apoptosis of BC cells triggered by ORY-1001 intervention were partially abolished. In conclusion, this paper has presented the first evidence to suggest that ORY-1001 inhibits proliferation and promotes apoptosis of TNBC cells by suppressing AR expression, which may constitute the theoretical basis for the clinical use of ORY-1001 in the treatment of this disease.