patients harboring Cav-1 mutations are more likely to undergo recurrence and metastas
 

(American Journal of Pathology. 2009;174:1650-1662.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080648
Caveolin-1 (P132L), a Common Breast Cancer Mutation, Confers Mammary Cell Invasiveness and Defines a Novel Stem Cell/Metastasis-Associated Gene Signature
<nobr></nobr>From the Departments of Cancer Biology,^* and Medical Oncology,^¶ Kimmel Cancer Center, and the Stem Cell Biology and Regenerative Medicine Center,^{http://ajp.amjpathol.org/math/dagger.gif} Thomas Jefferson University, Philadelphia, Pennsylvania; the Muscular and Neurodegenerative Disease Unit,^{http://ajp.amjpathol.org/math/Dagger.gif} University of Genoa and G. Gaslini Pediatric Institute, Genoa, Italy; and the Département de Biologie du Cancer,^{http://ajp.amjpathol.org/math/sect.gif} Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104 CNRS/U596 INSERM/Université Louis Pasteur, Strasbourg, France

<!-- ABS --> Here we used the Met-1 cell line in an orthotopic transplantationmodel in FVB/N mice to dissect the role of the Cav-1(P132L)mutation in human breast cancer. Identical experiments wereperformed in parallel with wild-type Cav-1. Cav-1(P132L) up-regulatedthe expression of estrogen receptor-http://ajp.amjpathol.org/math/agr.gif as predicted, because onlyestrogen receptor-http://ajp.amjpathol.org/math/agr.gif-positive patients have been shown to harborCav-1(P132L) mutations. In the context of primary tumor formation,Cav-1(P132L) behaved as a loss-of-function mutation, lackingany tumor suppressor activity. In contrast, Cav-1(P132L) causedsignificant increases in cell migration, invasion, and experimentalmetastasis, consistent with a gain-of-function mutation. Toidentify possible molecular mechanism(s) underlying this invasivegain-of-function activity, we performed unbiased gene expressionprofiling. From this analysis, we show that the Cav-1(P132L)expression signature contains numerous genes that have beenpreviously associated with cell migration, invasion, and metastasis.These include i) secreted growth factors and extracellular matrixproteins (Cyr61, Plf, Pthlh, Serpinb5, Tnc, and Wnt10a), ii)proteases that generate EGF and HGF (Adamts1 and St14), andiii) tyrosine kinase substrates and integrin signaling/adapterproteins (Akap13, Cdcp1, Ddef1, Eps15, Foxf1a, Gab2, Hs2st1,and Itgb4). Several of the P132L-specific genes are also highlyexpressed in stem/progenitor cells or are associated with myoepithelialcells, suggestive of an epithelial-mesenchymal transition. Theseresults directly support clinical data showing that patientsharboring Cav-1 mutations are more likely to undergo recurrenceand metastasis.