ADAM12-L confers acquired 5-fluorouracil resistance in breast cancer cells

Abstract

5-FU-based combinatory chemotherapeutic regimens have been routinely used for many years for the treatment of breast cancer patients. Recurrence and chemotherapeutic drug resistance are two of the most prominent factors that underpin the high mortality rates associated with most breast cancers (BC). Increasing evidence indicates that overexpression of ADAMs could correlate with cancer progression. However, the role of ADAMs in the chemoresistance of cancer cells has rarely been reported. In this study, we observed that 5-FU induces expression of the ADAM12 isoform ADAM12-L but not ADAM12-S in BC cells and in recurrent BC tissues. The overexpression of ADAM12-L in BC cells following 5-FU treatment results in the acquisition of resistance to 5-FU. ADAM12-L overexoression also resulted in increased levels of p-Akt but not p-ERK. These alterations enhanced BC cell growth and invasive abilities. Conversely, ADAM12 knockdown attenuated the levels of p-Akt and restored 5-FU sensitivity in 5-FU-resistant BC cells. ADAM12 knockdown also reduced BC cell survival and invasive abilities. These findings suggest that ADAM12-L mediates chemoresistance to 5-FU and 5-FU-induced recurrence of BC by enhancing PI3K/Akt signaling. The results of this study suggest that specific ADAM12-L inhibition could optimize 5-FU-based chemotherapy of BC, thereby preventing BC recurrence in patients.