Estrogen receptor alpha deletion enhances the metastatic phenotype of Ron overexpressing mammary tumors in mice.
BACKGROUND
The receptor tyrosine kinase family includes many transmembrane proteins with diverse physiological and pathophysiological functions. The involvement of tyrosine kinase signaling in promoting a more aggressive tumor phenotype within the context of chemotherapeutic evasion is gaining recognition. The Ron receptor is a tyrosine kinase receptor that has been implicated in the progression of breast cancer and evasion of tamoxifen therapy.


RESULTS
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.


CONCLUSIONS
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.
Department of Cancer and Cell Biology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0521, USA.
Aaron M
AM
Marshall
Rebecca J
RJ
McClaine
Devikala
D
Gurusamy
Jerilyn K
JK
Gray
Kara E
KE
Lewnard
Sohaib A
SA
Khan
Susan E
SE
Waltz
D000818:Animals; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
D047628:Estrogen Receptor alpha; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases