Yu S, Cai X, Wu C, Liu Y, Zhang J, Gong X, Wang X, Wu X, Zhu T, Mo L, Gu J, Yu Z, Chen J, Thiery JP, Chai R, Chen L. Targeting HSP90-HDAC6 Regulating Network Implicates Precision Treatment of Breast Cancer. Int J Biol Sci 2017; 13(4):505-517. doi:10.7150/ijbs.18834. Available from http://www.ijbs.com/v13p0505.htm
Breast cancer is the leading cause of women death. Heat shock protein 90 (HSP90) and Histone deacetylase 6 (HDAC6) are promising anti-cancer drug targets. However, it's still unclear the applicability of anti-HSP90 and anti-HDAC6 strategies in precision treatment of breast cancer. In current study, we found that triple negative breast cancer (TNBC) cells, compared to T47D, an ERα+ breast cancer cell line, exhibited 7~40 times lower IC50 values, stronger cell cycle perturbation, increased cell apoptosis and stronger inhibition of cell migration upon 17-DMAG treatment, while T47D, compared to TNBC cells, expressed higher HDAC6 and showed stronger anti-cancer response upon treatment of Tubacin. Mechanically, 17-DMAG treatment inhibited a complex network consists at least ERK, AKT, and Hippo pathway in TNBC cells, and higher expression of HDAC6 inhibited HSP90 activity via deacetylating HSP90. Furthermore, we found higher HDAC6 expression level in tamoxifen-resistance T47D than that in T47D, and Tubacin treatment suppressed the growth of tamoxifen-resistant cells in vivo. Our data suggested that anti-HSP90 and anti-HDAC6 are promising strategies to treat TNBC and ERα+ breast cancers respectively, and anti-HDAC6 can be considered during treatment of tamoxifen-resistance breast cancers.
This work was funded by the National Basic Research Program of China (973 Program, No. 2015CB965000 to L. Chen and 2013CB911300 to J. Chen), National Natural Science Foundation of China (No. 81572712 & 81272260 to L. Chen), the Fundamental Research Funds for the Central Universities (No.3231005410 to L. Chen), grants from the National Natural Science Foundation of China (No. 81572928 & 81272469 to R. Chai) and the clinical special project for Natural Science Foundation of Jiangsu Province (No. BL2012016 to J. Chen), Jiangsu Natural Science Foundation Outstanding Youth Foundation (No. SBK2016030027 to L. Chen), and the Six talent peaks project in Jiangsu Province (No. 2015-JY-002 to L. Chen).