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
] 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
]. 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
Ron is a cell surface RTK related to the c-Met receptor that has been identified as an oncogene in the development and growth of human epithelial tumors [9
]. In the developing mammary gland, Ron is expressed during the pubertal growth stages, and then again during pregnancy and lactation, and its expression remains low in quiescent glands [10
]. In normal mammary development, genetic loss of Ron signaling has been shown to alter mammary gland branching morphogenesis during puberty [10
]. In cell lines, wild-type Ron overexpression is associated with induction of oncogenic properties, including malignant transformation, proliferation, and migration [11
]. Overexpression of Ron in transgenic mouse models of both lung and breast cancer is associated with tumorigenesis in both organs [12
]; while deletion of Ron in transgenic mice expressing polyoma virus middle T antigen caused a significant reduction in breast tumor formation and growth [14
]. Additionally, Ron is known to be upregulated in a number of human epithelial cancers, including breast, lung, stomach, colon, pancreas, and prostate. Specifically, Ron is highly expressed in approximately 50% of human breast cancers [15
]. Given the important role of Ron in human and mouse tumorigenesis, identifying the functions and signaling pathways associated with this RTK may provide essential clues to combat disease progression.
Recent data has shown that Ron activation leads to the phosphorylation and activation ERα. In this case, exogenous overexpression of Ron or ligand activation of endogenous Ron led to enhanced survival of several ERα-positive breast cancer cell lines in the presence of the anti-estrogen therapy tamoxifen [4
]. Estrogen receptor alpha and its ligand estrogen are important regulators of mammary gland development and breast carcinogenesis. During development ERα is critical for peripubertal ductal elongation, and is a permissive factor in alveolar expansion during pregnancy [16
]. In cancer, ERα transcriptional programming provides survival and growth stimulation that is advantageous for tumors and the majority of human breast cancers express ERα. Consequently, ERα is the target of a family of anti-estrogen pharmacological compounds including tamoxifen. Although tamoxifen treatment is often initially successful at preventing the proliferative effect of estrogen on ERα, the preponderance of patients develop tamoxifen-resistance [5
] and the recurrent tumors tend to be more aggressive [17
]. Tamoxifen resistance has become a major obstacle to effective treatment of ERα-positive breast cancer.
Complementing previously published work, we show here that Ron is overexpressed and correlated with early stage ERα-positive breast cancers. To directly demonstrate the effect of ERα inactivation has on breast cancer, in the presence of Ron, we have created ERα -replete and ERα -conditionally deficient animals on a Ron overexpressing background. We show for the first time that mammary-specific ERα deletion increases breast tumor latency, but also leads to a more metastatic phenotype. Interestingly, these studies suggest a negative consequence of anti-estrogen therapy in Ron expressing tumors on the promotion of metastasis.