Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis in breast cancer stem-like cells (CSC) that promotes malignant progression. Using genome-wide ChIP-seq and RNA expression profiling, we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor (OBRhi). Inhibiting the STAT3/G9a pathway restored expression of miR-200c, which in turn reversed the CSC phenotype to a more differentiated epithelial phenotype. In a rat model of breast cancer driven by diet-induced obesity, STAT3 blockade suppressed the CSC-like OBRhi population and abrogated tumor progression. Together, our results show how targeting STAT3-G9a signaling regulates CSC plasticity during obesity-related breast cancer progression, suggesting a novel therapeutic paradigm to suppress CSC pools and limit breast malignancy.

Purpose: Oncolytic adenoviruses are attractive therapeutics for cancer because they selectively replicate in tumors. However, targeting tumor metastasis remains a major challenge for current virotherapy for cancer. Oct-3/4 is specifically expressed in embryonic stem cells and tumor cells. Oct-3/4 highly expressed in cancer cells may be a potential target for cancer therapy. We developed an E1B-55 kDa–deleted adenovirus, designated Ad.9OC, driven by nine copies of Oct-3/4 response element for treating Oct-3/4–expressing metastatic bladder cancer. Experimental Design: We examined the expression of Oct-3/4 in human bladder tumor tissues and bladder cancer cell lines. We also evaluated the cytolytic and antitumor effects of Ad.9OC on bladder cancer cells in vitro and in vivo. Results: Oct-3/4 expression was detected in bladder cancer cell lines, as well as in human bladder tumor tissues. Notably, Oct-3/4 expression was higher in metastatic compared with nonmetastatic bladder cancer cells. Ad.9OC induced higher cytolytic activity in metastatic bladder cancer cells than in their nonmetastatic counterparts, whereas it did not cause cytotoxicity in normal cells. Pharmacologic and short hairpin RNA–mediated Oct-3/4 inhibition rendered bladder cancer cells more resistant to Ad.9OC-induced cytolysis. Replication of Ad.9OC was detected in murine bladder cancer cells and bladder tumor tissues. We also showed the effectiveness of Ad.9OC for treating bladder cancer in subcutaneous, as well as metastatic, bladder tumor models. Conclusions: Ad.9OC may have therapeutic potential for treating Oct-3/4–expressing tumors. Especially, metastatic bladder tumors are good target for Ad.9OC treatment. Because Oct-3/4 is expressed in a broad spectrum of cancers, Ad.9OC may be broadly applicable.

Ultrasonic filing with 0.2% chlorhexidine as an irrigant is effective for disinfection of the root canal and can shorten the duration for apical barrier formation in necrotic permanent incisors treated with calcium hydroxide apexification.

Epigenetic control plays a key role in regulation of tumorigenesis in response to the microenvironmental stimuli, however, the regulatory mechanism involved in the process is largely unclear. We now report that a critical epigenetic regulator miR-205 is repressed by Jagged1, a ligand shown to be secreted from the tumor stroma, to promote the cancer stem cell phenotype. Loss of miR-205 in mammary epithelial cells leads to epithelial-mesenchymal transition, disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, mice deficient of miR-205 spontaneously develop mammary lesions, and activation of miR-205 significantly diminishes the breast cancer stemness. These data provides the first evidence to link microenvironment and microRNA regulation to the disrupted epithelial polarity and aberrant stem cell division, leading to an expansion of the stem cell population and tumorigenesis. Together, this study elucidates a new role for miR-205 in regulation of stem cell fate, providing a promising therapeutic target to eradicate the genesis of breast cancer. Citation Format: Meng-Ju Wu, Chi-Hong Chao, Chao-Ching Chang, Chun-Ju Chang. Dysregulated miR-205 signaling promotes symmetric division of self-renewing mammary stem cells and mammary tumorigenesis. [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 4345. doi:10.1158/1538-7445.AM2014-4345