Ductal carcinoma in situ (DCIS) is a key step that precedes the earliest stages of tumor cells spreading in breast cancer. DCIS represents the ideal target in a strategy to prevent progression to invasive breast cancer. However, the biology of DCIS is relatively poorly understood. S100A7 is a Ca2+ - binding protein, which is one of the most highly expressed genes in DCIS, and is believed to influence tumor progression through interaction with Jab1 and stimulation of Jab1 related activities. The epidermal growth factors (EGF) have also been shown to be important in normal and breast cancer biology, exerting their effects through tyrosine kinase growth factor receptors. These receptors, including epidermal growth factor receptor (EGFR), S100A7, and Jab1 are frequently expressed in DCIS and associated with the same estrogen receptor negative (ER-ve) tumor phenotype.

To investigate the possible interaction of S100A7-Jab1 and EGFR sigalling pathways in breast cancer progression, we examined these pathways in breast cancer cell lines MDA-MB-231, MDA-MB-231-FD3 (S100A7 transfected), and MDA-MD-468. EGF increased S100A7 expression in MDA-MB-231-FD3 and MDA-MD-468 cell lines compared to MDA-MB-231 and also increases Jab1 translocation from cytoplasm to nuclear cellular compartments. The effect of EGF on S100A7 occurs predominantly at the level of protein levels and correlates with the relative levels of EGFR in these cell lines. Inhibition of EGFR by EGF receptor kinase inhibitor, AG 1478, also reduced S100A7 expression and blocked Jab1 redistribution to nucleus. Jab1 redistribution was also prevented by pretreatment with PD98059, an ERK pathway inhibitor.

Our results show that EGF activation of EGFR regulates Jab1 and that this pathway interacts with the S100A7-Jab1 pathway through both regulation of S100A7 and synergistic effects on Jab1. Exploration of the relevance of these observations in breast cancer tissues is in progress. We conclude that the interaction between the EGFR and S100A7-Jab1 pathways which are both prevalent in DCIS, may play an important role in early breast cancer progression. Understanding these interactions may have an important role in the development of novel anticancer targeted therapies in breast cancer progression in DCIS.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA