Abstract 1314: Estrogen receptor-α is activated in breast ductal epithelial cells by CCN5 in CCN5-conditional tri-transgenic mice

Abstract

Estrogen receptor-alpha (ER-α) is localized in the nuclei of approximately 3-7% of normal resting breast epithelial cells with a higher proportion in lobular cells than in ductal. This number is significantly increased in atypical ductal hyperplasia, ductal carcinoma in situ (DCIS), pure intraductal carcinoma, and intraductal carcinoma with invasive duct carcinoma. Despite having this information for last 15 years, it is still uncertain how ER-α is activated in the nuclei of breast epithelial cells. CCN5/WISP-2, a member of the CCN (Cysteine-rich61/Connective Tissue Growth Factor/Nephroblastoma overexpressed) family of growth factors, is becoming an increasingly important focus in breast cancer research. CCN5/WISP-2 is a two-faced signaling molecule and plays differently in breast carcinogenesis under different micro-environmental setups. Our previous studies have shown that the transcriptional and translational activation of the WISP-2/CCN5 gene is a characteristic of estrogen receptor positive non-invasive breast tumor cell lines. Expression of the WISP-2/CCN5 gene was virtually undetected in non-transformed mammary epithelial cells. Moreover, multiple studies suggest a fine tune between CCN5 signaling and ER-α pathways, but this has not yet been fully elucidated. The main objective of this work was to establish the effect of excessive activation of CCN5 on the ER-α signaling. To do so, we generated a tri-transgenic inducible mouse model that overexpresses CCN5 under the Doxycycline (dox) environment. After the confirmation of the conditional expression of CCN5 in a mammary-specific and dox-dependent manner, morphology as well as the status of ER-α was evaluated. We found that induced expression of CCN5 by Dox in breast epithelial cells significantly increased ER-α expression and activity along with no morphological changes. Collectively, these studies indentify CCN5 as a regulator of ER-α in breast epithelial cells in a tri-transgenic mouse model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1314. doi:10.1158/1538-7445.AM2011-1314

CCN5/WISP-2: A micromanager of breast cancer progression

“…Although CCN5/WISP-2 has been recognized as an estrogen-response gene by multiple studies, regulation of ER-α by CCN5/WISP-2 has also been appreciated by recent in vitro study (Fritah et al 2008) and a CCN5-conditional tri-transgenic mouse model (Majumder et al 2011). The in vitro studies showed that the knocking down of CCN5 expression in breast cancer cells markedly reduced the expression of ER-α expression.…”