Estrogen receptor alpha deletion enhances the metastatic phenotype of Ron overexpressing mammary tumors in mice

Here, we report that Ron expression is correlated with in situ, estrogen receptor alpha (ERα)-positive tumors, and is higher in breast tumors following neoadjuvant tamoxifen therapy. We also demonstrate that the majority of mammary tumors isolated from transgenic mice with mammary specific-Ron overexpression (MMTV-Ron mice), exhibit appreciable ER expression. Moreover, genetic-ablation of ERα, in the context of Ron overexpression, leads to delayed mammary tumor initiation and growth, but also results in an increased metastasis.Ron receptor overexpression is associated with ERα-positive human and murine breast tumors. In addition, loss of ERα on a Ron overexpressing background in mice leads to the development of breast tumors which grow slower but which exhibit more metastasis and suggests that targeting of ERα, as in the case of tamoxifen therapy, may reduce the growth of Ron overexpressing breast cancers but may cause these tumors to be more metastatic.To date, the most successful pharmacological therapies specifically targeting breast cancer include anti-estrogens and receptor tyrosine kinase (RTK) modulating drugs [1]. Accordingly, there have been numerous studies examining signaling paradigms between estrogen and RTK signaling pathways [2-4] which have provided evidence that RTKs are able to activate estrogen receptor alpha (ERα) in breast cancers independent of its ligand estrogen. This activation of ERα by RTKs leads to an ERα transcriptional program that enhances cell survival. The dependency of this activation on the RTK ligand is still an area of active investigation. More importantly, however, this signaling crosstalk between RTKs and ERα may predict resistance to anti-estrogen hormonal therapies, including tamoxifen [2,5]. Specifically, studies have shown that activation of EGFR, Her2, cMet, IGFR, RET and recently, Ron RTK, lead to phosphorylation and activation of ERα which enhances survival of breast cancer in the presence of anti-estrogen therapy [4,6-