(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
From the Departments of Cancer Biology,* and Medical Oncology,¶ Kimmel Cancer Center, and the Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, Philadelphia, Pennsylvania; the Muscular and Neurodegenerative Disease Unit, University of Genoa and G. Gaslini Pediatric Institute, Genoa, Italy; and the Département de Biologie du Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104 CNRS/U596 INSERM/Université Louis Pasteur, Strasbourg, France
Here we used the Met-1 cell line in an orthotopic transplantation
model in FVB/N mice to dissect the role of the Cav-1(P132L)
mutation in human breast cancer. Identical experiments were
performed in parallel with wild-type Cav-1. Cav-1(P132L) up-regulated
the expression of estrogen receptor-
as predicted, because only
estrogen receptor-
-positive patients have been shown to harbor
Cav-1(P132L) mutations. In the context of primary tumor formation,
Cav-1(P132L) behaved as a loss-of-function mutation, lacking
any tumor suppressor activity. In contrast, Cav-1(P132L) caused
significant increases in cell migration, invasion, and experimental
metastasis, consistent with a gain-of-function mutation. To
identify possible molecular mechanism(s) underlying this invasive
gain-of-function activity, we performed unbiased gene expression
profiling. From this analysis, we show that the Cav-1(P132L)
expression signature contains numerous genes that have been
previously associated with cell migration, invasion, and metastasis.
These include i) secreted growth factors and extracellular matrix
proteins (
Cyr61,
Plf,
Pthlh,
Serpinb5,
Tnc, and
Wnt10a), ii)
proteases that generate EGF and HGF (
Adamts1 and
St14), and
iii) tyrosine kinase substrates and integrin signaling/adapter
proteins (
Akap13,
Cdcp1,
Ddef1,
Eps15,
Foxf1a,
Gab2,
Hs2st1,
and
Itgb4). Several of the P132L-specific genes are also highly
expressed in stem/progenitor cells or are associated with myoepithelial
cells, suggestive of an epithelial-mesenchymal transition. These
results directly support clinical data showing that patients
harboring Cav-1 mutations are more likely to undergo recurrence
and metastasis.