Breast cancer is the leading cause of cancer mortality in women with a high incidence of recurrence and eventual treatment failure. The last decade has yielded substantial evidence that cancer stem cells (CSCs) contribute to tumor relapse, metastasis and chemoresistance. CSCs are regulated by complex interactions with the components of the tumor microenvironment through networks of cytokines and growth factors, including the IL6-STAT3 signaling pathway. Although the IL6 signaling pathway has been extensively characterized, the network of effector genes and proteins that regulates the CSC population remains poorly understood. Here, we show that ATOH8 is a downstream effector of IL6-STAT3 signaling which promotes the stemness of breast cancer cells. ATOH8 is significantly increased after IL6 stimulation and can be directly regulated by STAT3. Ectopic expression of ATOH8 in 4T1 or T-47D cells is sufficient to increases the CSC sub-population and enhances tumorogenesis in mice. Mechanistically, ATOH8 promotes the expression of Oct3/4 and Nanog, key regulators of CSC renewed. Accordingly, Knock-down of ATOH8 in EMT6 or MDA-MB-231 cells is associated with decreased expression of Oct3/4 and Nanog and reduces the CSC sub-population. In patients, ATOH8 expression is a negative prognostic indicator for overall survival. Together, the results identify ATOH8 as a downstream effector of IL6-STAT3 signaling that compromises long-term surviving in breast cancer.

Citation Format: Antao Chang, Yanan Chen, Wenzhi Shen, Ruifang Gao, Wei Zhou, Yunping Luo, Na Luo, Dwayne Stupack, Rong Xiang. The basic helix-loop-helix (bHLH) transcriptional factor ATOH8 promotes the stemness of breast cancer cells via Oct4 and Nanog. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1956. doi:10.1158/1538-7445.AM2014-1956