Study On The Effects Of ER-α36and SOX4in Er Negative Breast Cancer

Breast cancer is the most common malignant tumor and is the leading cause of cancer-related deaths in women worldwide. Estrogen receptor (ER; i.e., ER-a66) expression is an important prognostic and predictive factor of breast cancer and has relevant implications for breast cancer biology. Approximately70%of breast cancers are ER-positive and patients with ER-negative tumors had a shorter disease-free interval and overall survival than patients with ER-positive tumors. Although significant progress has been made in the development of endocrine therapies that target estrogen or ER for ER-positive tumors, there is no valid target for ER-negative tumors. Identifying novel targets for ER-negative breast cancers is therefore an urgent topic of research these days.In this study, we mainly investigated the effects of estrogen receptor-alpha36(ER-α36) and SOX4in tumor cell growth, metastasis and response to chemotherapies, and evaluated their potential as new therapeutic targets in ER negative breast cancer.Part ⅠER-a36is a variant of ER-α that has been found to be expressed in conventional ER (ER-a66)-negative breast cancer cell lines and human breast cancer samples. In this study, we found that, using immunohistochemical study, ER-α36expression was significantly higher in ER-negative tumors than in ER-positive tumors although the expression was not associated with other clinicopathological characteristics including age, Her-2status, tumor size, lymph node status, or tumor stage. We then constructed an ER-a36-specific microRNA vector by multi-microRNA hairpin method, and established stable ER-a36knockdown cells. We found that the knockdown cells were more sensitive to paclitaxel; the c-Jun N-terminal kinese pathway appeared to be involved in the mechanism. Downregulation of ER-a36also resulted in decreased migration and invasion. These changes were estrogen independent. Our findings indicated that targeting ER-a36may be a strategy for the treatment of ER-negative breast cancers.Part IISOX4is a transcription factor which was found to be expressed in many malignant tumors including breast cancer. In this study, we overexpressed SOX4by lentivirus in ER negative breast cancer cells and found that overexpression of SOX4increased the ability of migration and invasion in vitro and resulted in earlier and more tumor metastasis in vivo. We observed morphological and molecular changes consistent with epithelial-mesenchymal transition in SOX4overexpressing cells. We also demonstrated that expression of CXCR7was significantly increased in SOX4overexpressing cells and inhibition of CXCR7with its inhibitor CCX771abolished the increased migration and invasion associated with SOX4overexpression, indicating that CXCR7is a target gene of SOX4and plays a role in breast cancer metastasis. We found that cells with high expression of SOX4were more sensitive to Paclitaxel, indicating that Paclitaxel might be effective for those tumors with high expression of SOX4. We also found that SOX4could promote cell proliferation in some breast cancer cell lines.