Fibroblast Growth Factor Receptor 1–Transformed Mammary Epithelial Cells Are Dependent on RSK Activity for Growth and Survival

Departments of ¹Cell Biology and ²Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts; ³Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; and ⁴Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands

^* To whom correspondence should be addressed. E-mail: joan_brugge{at}hms.harvard.edu.

	Abstract

Fibroblast growth factor receptor 1 (FGFR1) is frequently amplified and highly expressed in lobular carcinomas of the breast. In this report, we evaluated the biological activity of FGFR1 in a wide range of in vitro assays. Conditional activation of FGFR1 in the nontransformed MCF10A human mammary cell line, MCF10A, resulted in cellular transformation marked by epidermal growth factor–independent cell growth, anchorage-independent cell proliferation and survival, loss of cell polarity, and epithelial-to-mesenchymal transition. Interestingly, small-molecule or small interfering RNA inhibition of ribosomal S6 kinase (RSK) activity induced death of the FGFR1-transformed cells, but not of the parental MCF10A cell line. The dependence of FGFR1-transformed cells on RSK activity was further confirmed in cell lines derived from mouse and human lobular carcinomas that possess high FGFR1 activity. Taken together, these results show the transforming activity of FGFR1 in mammary epithelial cells and identify RSK as a critical component of FGFR1 signaling in lobular carcinomas, thus implicating RSK as a candidate therapeutic target in FGFR1-expressing tumors. [Cancer Res 2009;69(6):2244–51]

Key Words: Lobular Carcinoma, FGFR1, RSK, inducible dimerization, three-dimensional culture

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				Correction: Article on FGFR1 Expression Induces RSK Dependency Cancer Res., August 1, 2009; 69(15): 6366 - 6366. [Full Text] [PDF]