The potential effect of triterpenoids in triple negative breast cancer

Triple negative breast cancer (TNBC) classifies as lacking expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her-2). TNBC mainly represents basal-like subtype, which consists 80% of TNBC. TNBC has the poorest prognosis and the current standard therapy is chemotherapy. Triterpenoids have been reported as chemopreventive agents for many cancers, including breast cancer. Since natural triterpenoids such as oleanolic acid and ursolic acid were reported to have weak anti-inflammation and anti-cancer effects, synthetic oleanane triterpenoids have been developed to increase biological activity. One such synthetic oleanane triterpenoid, 2-cyano-3, 12-di oxooleana-1, 9-dien-28-oic acid-Imidazolide (CDDO-Im), is a promising agent with potent anti-proliferation and apoptosis activity against various cancers, but the mechanism of these effects remains unclear. In the first part of the project, CDDO-Im inhibited the cell growth, induced G2/M arrest and apoptosis in triple negative breast cancer SUM159 cells. Western blot analysis showed CDDO-Im down-regulated cyclin D1, up-regulated apoptosis markers, and increased DNA damage checkpoint markers that lead to G2/M arrest. Moreover, CDDO-Im repressed the protein level of CD44, pSTAT3 and pNFκB in a dose dependent manner, suggesting that CD44-STAT3 or NFκB signaling may play an important role for the chemopreventive action of CDDO-Im in triple negative breast cancer. In the second part of the project, CDDO-Im decreased CD44+/CD24- cell population in SUM159 monolayers and CD44+/CD24-/ESA+ cell population, which presents as cancer stem cell (CSC) population, in SUM159 mammospheres. CDDO-Im also reduced the number and size of primary and secondary mammospheres in a dose dependent manner. In conclusion, CDDO-Im inhibited TNBC by inducing the G2/M arrest and apoptosis. CDDO-Im had anti-cancer stem cell effect by decreasing the CSC population. These findings suggest the potential use of CDDO-Im for the chemoprevention of TNBC and warrant further in vivo studies and clinical evaluation.M.S.Includes bibliographical referencesby Janice Janing Li