The Ron receptor tyrosine kinase negatively regulates mammary gland branching morphogenesis.

Full Abstract

The Ron receptor tyrosine kinase is expressed in normal breast tissue and is overexpressed in approximately 50% of human breast cancers. Despite the recent studies on Ron in breast cancer, nothing is known about the importance of this protein during breast development. To investigate the functional significance of Ron in the normal mammary gland, we compared mammary gland development in wild-type mice to mice containing a targeted ablation of the tyrosine kinase (TK) signaling domain of Ron (TK-/-). Mammary glands from RonTK-/- mice exhibited accelerated pubertal development including significantly increased ductal extension and branching morphogenesis. While circulating levels of estrogen, progesterone, and overall rates of epithelial cell turnover were unchanged, significant increases in phosphorylated MAPK, which predominantly localized to the epithelium, were associated with increased branching morphogenesis. Additionally, purified RonTK-/- epithelial cells cultured ex vivo exhibited enhanced branching morphogenesis, which was reduced upon MAPK inhibition. Microarray analysis of pubertal RonTK-/- glands revealed 393 genes temporally impacted by Ron expression with significant changes observed in signaling networks regulating development, morphogenesis, differentiation, cell motility, and adhesion. In total, these studies represent the first evidence of a role for the Ron receptor tyrosine kinase as a critical negative regulator of mammary development.

Author information

Author/s: Meyer, Sara E (SE); Zinser, Glendon M (GM); Stuart, William D (WD); Pathrose, Peterson (P); Waltz, Susan E (SE);

Affiliation: Department of Cancer and Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, 3125 Eden Ave, Cincinnati, OH 45267-0521, USA.

Grants: CA-100002 (Agency:NCI NIH HHS) ; DK-064403 (Agency:NIDDK NIH HHS) ; T32-CA59268 (Agency:NCI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Developmental biology (Dev Biol), published in United States. (Language: eng)

Reference: 2009-Sep; vol 333 (issue 1) : pp 173-85

Dates: Created 2009/08/17; Completed 2009/11/13;

PMID: 19576199, status: MEDLINE (last retrieved date: 11/15/2009)

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