Fibroblast growth factor receptor 1-transformed mammary epithelial cells are dependent on RSK activity for growth and survival.
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.
Xian
Wa
W
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Pappas
Leontios
L
Pandya
Darshan
D
Selfors
Laura M
LM
Derksen
Patrick W
PW
de Bruin
Michiel
M
Gray
Nathanael S
NS
Jonkers
Jos
J
Rosen
Jeffrey M
JM
Brugge
Joan S
JS
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D042361:Mammary Glands, Human / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
D051496:Receptor, Fibroblast Growth Factor, Type 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa