Erbb3 as a Novel Target of HDAC Inhibitor against ErbB2-overexpressing Breast Cancers

• 作 者: BolinLiu;
• 机 构: University of Colorado Denver School of Medicine Aurora, CO USA
• 出 处: BIT‘s2nd Annual World Cancer Congess-2009 (2009第二届癌症大会)
• 发表日期: 2009年期

　　Inhibitors of the histone deacetylase (HDAC) have been found to possess anticancer activity in a variety of tumor cell models.One HDAC inhibitor SNDX-275 has been shown to inhibit proliferation and induce apoptosis in human breast cancer cells through induction of transforming growth factor type Ⅱ receptor or TRAIL expression, or degradation of DNA methyltransferase Ⅰ.There is no report indicating whether SNDX-275 has any preference against different subtypes of breast cancers.In the current studies, we have investigated the potential therapeutic efficacy of SNDX-275 on erbB2-overexpressing and basal (also called "triple negative") breast cancer cells.SNDX-275 induced apoptosis and cell cycle Gl arrest in erbB2-overexpressing SKBR3, BT474, and MDA-MB-453 cells, but it had little effect on apoptosis induction and cell cycle progression in basal breast cancer MDA-MB-468, MDA-MB-231, and BT20 cells.Upon SNDX-275 treatment, the levels of P-erbB2, P-erbB3, P-MAPK, and P-Akt in SKBR3, BT474 and MDA-MB-453 cells were significantly decreased, which was associated with a rapid diminish of erbB3 protein and a less impressive reduction in erbB2 receptor, suggesting that SNDX-275 inhibited erbB2 tyrosine kinase activity and the downstream signaling for cell survival/proliferation mainly through downregulation of erbB3 expression.Moreover, elevated expression of erbB3 via transfection with erbB3-containing expression vector abrogated SNDX-275-induced inactivation of the downstream signaling, apoptosis, and cell cycle arrest, whereas knockdown of erbB3 expression with specific shRNAs dramatically enhanced the efficacy of SNDX-275-induced inactivation of the downstream signaling, apoptosis, and cell cycle arrest in SKBR3 and BT474 cells.Our results demonstrated that SNDX-275 selectively inhibited cell signaling and induced apoptosis and cell cycle G1 arrest in erbB2-overexpressing breast cancer ells through downregulation of erbB3 expression.SNDX-275 may be developed as a novel therapeutic agent targeting erbB3 in erbB2-overexpressing breast cancers.