Caveolin-1 Promotes Tumor Progression in an Autochthonous Mouse Model of Prostate Cancer

Abstract

Caveolin-1 (Cav-1) is the primary structural component of caveolae and is implicated in the processes of vesicular transport, cholesterol balance, transformation, and tumorigenesis. Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo, Cav-1 is expressed at increased levels in human prostate cancer. To investigate the role of Cav-1 in prostate cancer onset and progression, we interbred Cav-1(-/-) null mice with a TRAMP (transgenic adenocarcinoma of mouse prostate) model that spontaneously develops advanced prostate cancer and metastatic disease. We found that, although the loss of Cav-1 did not affect the appearance of minimally invasive prostate cancer, its absence significantly impeded progression to highly invasive and metastatic disease. Inactivation of one (+/-) or both (-/-) alleles of Cav-1 resulted in significant reductions in prostate tumor burden, as well as decreases in regional lymph node metastases. Moreover, further examination revealed decreased metastasis to distant organs, such as the lungs, in TRAMP/Cav-1(-/-) mice. Utilizing prostate carcinoma cell lines (C1, C2, and C3) derived from TRAMP tumors, we also showed a positive correlation between Cav-1 expression and the ability of these cells to form tumors in vivo. Furthermore, down-regulation of Cav-1 expression in these cells, using a small interfering RNA approach, significantly reduced their tumorigenic and metastatic potential. Mechanistically, we showed that loss or down-regulation of Cav-1 expression results in increased apoptosis, with increased prostate apoptosis response factor-4 and PTEN levels in Cav-1(-/-) null prostate tumors. Our current findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during prostate carcinogenesis, rather than as a tumor suppressor. Caveolin-1 (Cav-1) is the primary structural component of caveolae and is implicated in the processes of vesicular transport, cholesterol balance, transformation, and tumorigenesis. Despite an abundance of data suggesting that Cav-1 has transformation suppressor properties both in vitro and in vivo, Cav-1 is expressed at increased levels in human prostate cancer. To investigate the role of Cav-1 in prostate cancer onset and progression, we interbred Cav-1(-/-) null mice with a TRAMP (transgenic adenocarcinoma of mouse prostate) model that spontaneously develops advanced prostate cancer and metastatic disease. We found that, although the loss of Cav-1 did not affect the appearance of minimally invasive prostate cancer, its absence significantly impeded progression to highly invasive and metastatic disease. Inactivation of one (+/-) or both (-/-) alleles of Cav-1 resulted in significant reductions in prostate tumor burden, as well as decreases in regional lymph node metastases. Moreover, further examination revealed decreased metastasis to distant organs, such as the lungs, in TRAMP/Cav-1(-/-) mice. Utilizing prostate carcinoma cell lines (C1, C2, and C3) derived from TRAMP tumors, we also showed a positive correlation between Cav-1 expression and the ability of these cells to form tumors in vivo. Furthermore, down-regulation of Cav-1 expression in these cells, using a small interfering RNA approach, significantly reduced their tumorigenic and metastatic potential. Mechanistically, we showed that loss or down-regulation of Cav-1 expression results in increased apoptosis, with increased prostate apoptosis response factor-4 and PTEN levels in Cav-1(-/-) null prostate tumors. Our current findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during prostate carcinogenesis, rather than as a tumor suppressor. Caveolin-1 (Cav-1) 1The abbreviations used are: Cav-1, caveolin-1; TRAMP, transgenic adenocarcinoma of mouse prostate; siRNA, small interfering RNA; PCNA, proliferating cell nuclear antigen; WT, wild-type; PBS, phosphate-buffered saline; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick-end label; KO, knock-out; HET, heterozygous; PIN, prostatic intraepithelial neoplasia; ERK, extracellular signal-regulated kinase; Par4, prostate apoptosis response factor-4. is the principal structural component and marker protein of caveolae, 50-100-nm flask-shaped invaginations of the plasma membrane. Cav-1 was first identified as a tyrosine-phosphorylated substrate when avian fibroblasts were transformed with the v-Src oncogene, suggesting that Cav-1 may have a critical role in modulating cellular transformation (1Glenney Jr., J.R. J. Biol. Chem. 1989; 264: 20163-20166Abstract Full Text PDF PubMed Google Scholar). To date, three caveolin family members have been identified, with diverse tissue expression patterns in various organisms ranging from mammals and amphibians to the nematode. Such ubiquity in higher organisms insinuates the importance of the caveolin gene family for normal physiology (2Williams T.M. Lisanti M.P. Genome Biol. 2004; 5: 214.1-214.8Crossref Scopus (365) Google Scholar). The majority of caveolin-related research has focused on caveolin-1 as the prototypical member, and the past decade has brought considerable advances in our understanding of the functions of Cav-1. Thus far, Cav-1 has been implicated in many cellular processes, from signal transduction and vesicular transport to cholesterol homeostasis and lipid transport (reviewed in Ref. 3Cohen A.W. Hnasko R. Schubert W. Lisanti M.P. Physiol. Rev. 2004; 84: 1341-1379Crossref PubMed Scopus (737) Google Scholar). Concurrently, a growing field of research is beginning to define the role of the caveolins in the development of human cancers. Identification of a novel function for Cav-1 in oncogenesis began with the demonstration that Cav-1 levels inversely correlated with soft agar growth in transformed NIH 3T3 fibroblasts (4Koleske A.J. Baltimore D. Lisanti M.P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1381-1385Crossref PubMed Scopus (472) Google Scholar). Subsequently, several groups have shown that recombinant expression of Cav-1 in certain human or mouse tumor-derived cell lines significantly inhibits their soft agar growth (5Lee S.W. Reimer C.L. Oh P. Campbell D.B. Schnitzer J.E. Oncogene. 1998; 16: 1391-1397Crossref PubMed Scopus (399) Google Scholar, 6Engelman J.A. Wykoff C.C. Yasuhara S. Song K.S. Okamoto T. Lisanti M.P. J. Biol. Chem. 1997; 272: 16374-16381Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar, 7Zhang W. Razani B. Altschuler Y. Bouzahzah B. Mostov K.E. Pestell R.G. Lisanti M.P. J. Biol. Chem. 2000; 275: 20717-20725Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 8Fiucci G. Ravid D. Reich R. Liscovitch M. Oncogene. 2002; 21: 2365-2375Crossref PubMed Scopus (250) Google Scholar). More recently, we and others have reported that Cav-1 has in vivo tumor suppressor properties in certain tissues, such as the mammary gland and skin, utilizing various murine animal models (9Williams T.M. Cheung M.W. Park D.S. Razani B. Cohen A.W. Muller W.J. Di Vizio D. Chopra N.G. Pestell R.G. Lisanti M.P. Mol. Biol. Cell. 2003; 14: 1027-1042Crossref PubMed Scopus (135) Google Scholar, 10Capozza F. Williams T.M. Schubert W. McClain S. Bouzahzah B. Sotgia F. Lisanti M.P. Am. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, Oncogene. 2004; PubMed Scopus Google Scholar, T.M. F. J. Muller W.J. Chopra N.G. Pestell R.G. Lisanti M.P. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). using a mouse model of mammary we have shown that Cav-1 expression inhibits the progression of mammary as well as the development of primary mammary tumors and metastases. of human in the gene have been identified in as well as cell S. T. Y. Y. T. M. Google Scholar, Park G. J. 2004; Google and gene to a tumor suppressor on is in a of human (reviewed in Ref. B. Lisanti M.P. J. PubMed Scopus Google Scholar). with these Cav-1 protein levels in a of human and mammary B. Lisanti M.P. J. PubMed Scopus Google Scholar). Despite between Cav-1 and tumor is evidence that Cav-1 does not function in of human cancers. several groups have that Cav-1 protein expression levels in human and prostate S. R. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Lisanti M.P. M. Am. J. 2003; PubMed Scopus Google Scholar, S. J. G. Google Scholar, Y. M. T. T. S. S. 2002; PubMed Scopus Google Scholar, G. T.M. Park Y. M.W. 1998; Google Scholar, G. T.M. Google Scholar, T. G. S. J. A. S. S. 2003; PubMed Scopus Google Scholar). findings that Cav-1 does not have transformation suppressor in these further of human and prostate that Cav-1 with increased tumor invasive regional and decreased S. R. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Lisanti M.P. M. Am. J. 2003; PubMed Scopus Google Scholar, Y. M. T. T. S. S. 2002; PubMed Scopus Google Scholar, G. T.M. Google Scholar, T. G. S. J. A. S. S. 2003; PubMed Scopus Google Scholar). these results that Cav-1 has functions in certain tumor cell such as prostate has been cell with human prostate tumor-derived cell these prostate carcinoma cell Cav-1 to correlated with increased cell and increased metastatic Y. G. Park M. J. 1998; PubMed Scopus Google Scholar, G. S. T. Y. J. Google Scholar). these findings that Cav-1 has cell or tumor on its cellular Cav-1 expression the development of prostate in vivo. have focused on the of prostate cell we a well transgenic mouse model of prostate cancer, TRAMP (transgenic adenocarcinoma of mouse to the role of Cav-1 in modulating prostate in vivo. we interbred Cav-1(-/-) null Cav-1 with the well TRAMP mouse model F. D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: PubMed Scopus Google Scholar, J.R. R. Google Scholar, T.M. W.J. 2003; PubMed Scopus Google Scholar). to genetic loss of one (+/-) or both alleles (-/-) of Cav-1 prostate tumor development in an in vivo of TRAMP model has many prostate tumors to in their with to the growth and the of the for further on the and the of the TRAMP we that prostate tumors derived from TRAMP mice an of Cav-1 to human prostate cancers. More of one or both Cav-1 alleles significantly the progression of prostate carcinoma with to primary tumor and advanced metastatic disease. findings further with cell lines derived from TRAMP prostate tumors (C1, C2, and three TRAMP cell lines and the their and prostatic J.R. 1997; Google Scholar). these cell Cav-1 expression with tumor of Cav-1 gene expression in the TRAMP cell inhibits the processes of primary tumor growth and of both transgenic prostate tumors and cell tumors that loss of Cav-1 results in decreased cell as well as the of PTEN and our findings provide the first in vivo molecular genetic evidence that Cav-1 does indeed function as a tumor promoter during mouse prostate carcinogenesis, rather than as a tumor suppressor. we reported that Cav-1 has a tumor suppressor role in the mouse mammary gland T.M. F. J. Muller W.J. Chopra N.G. Pestell R.G. Lisanti M.P. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google our current results that Cav-1 has functions with to both and and to caveolin-1 and and were the of and their were as and and were as we T.M. F. J. Muller W.J. Chopra N.G. Pestell R.G. Lisanti M.P. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). were and in a at the for of were on a with to and used for were the for Cav-1 null mice were as (9Williams T.M. Cheung M.W. Park D.S. Razani B. Cohen A.W. Muller W.J. Di Vizio D. Chopra N.G. Pestell R.G. Lisanti M.P. Mol. Biol. Cell. 2003; 14: 1027-1042Crossref PubMed Scopus (135) Google Scholar). TRAMP mice the of the were from The and for the of the as on The the mice used in were in the Cav-1(-/-) null mice were interbred with TRAMP mice to three mice and TRAMP/Cav-1(-/-) mice. TRAMP mice from were for the TRAMP TRAMP transgenic mice were at of and a was on examination of the and tumors were and in for for and were and with and for was prostate tumor the prostate tissue was and for and were for metastasis lymph and were at and with and or for were with a and with with NIH were as the of metastatic as a of or cell lines (C1, C2, and C3) were from the cell lines were and derived from prostate and from mice J.R. 1997; Google Scholar). these cell lines and their prostate three cell lines and cell lines also form tumors in or is the cell that in soft cells the growing in vitro and in vivo, cells the growing and not form tumors in vivo J.R. 1997; Google Scholar). three cell lines were in with and The used for caveolin-1 down-regulation was with the of the of caveolin-1 was as a and used to a of and a were and the to the of cell lines and was as we T.M. F. J. Muller W.J. Chopra N.G. Pestell R.G. Lisanti M.P. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). and and were as we in (9Williams T.M. Cheung M.W. Park D.S. Razani B. Cohen A.W. Muller W.J. Di Vizio D. Chopra N.G. Pestell R.G. Lisanti M.P. Mol. Biol. Cell. 2003; 14: 1027-1042Crossref PubMed Scopus (135) Google Scholar, T.M. F. J. Muller W.J. Chopra N.G. Pestell R.G. Lisanti M.P. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). cells were to in and with a cells in of were the of and tumors were the mouse with cell cells in of were the of mice and tumors were were and with were using the is the and is cells in of of cell were the were in and and as for the transgenic dUTP of TRAMP and TRAMP prostate tumors or and tumors were with a to the in apoptosis were a using a To Cav-1 an role in prostate cancer progression, we interbred Cav-1(-/-) null mice with TRAMP mice mouse model of prostate to three of TRAMP transgenic and TRAMP/Cav-1(-/-) null mice. mice were for the TRAMP expression of the to the prostate the reported and J.R. R. Google TRAMP mice to the regional lymph of with and to distant such as the with J.R. R. Google Scholar). to both prostate and we mice from the three at of and a examination of the of TRAMP were in WT, HET, and Cav-1(-/-) mice. mice that to the of were from the of mice of mice and of mice of the and mice revealed that of these mice tumor burden, that advanced prostate cancer was the primary of the mice that did not significant prostate cancer suggesting that these mice from Caveolin-1 in from TRAMP Cav-1 is during the of mouse prostate carcinogenesis, we first on normal prostate tissue and prostate tumors derived from mice at of prostate tumors were from mice with a tumor and metastatic the advanced of these tumors. examination of these tumors also revealed that were prostate We first Cav-1 expression in normal prostate of the and was in the of prostate in for Cav-1 in the a that levels of Cav-1 the the majority of tumors from mice showed Cav-1 the prostate tumor cells, in to the and was with prostate tissue from Cav-1(-/-) mice and prostate tumors from TRAMP/Cav-1(-/-) mice Cav-1 was in these Cav-1(-/-) null results that Cav-1 is expressed at levels in prostate is significantly during the of transformed to the development of prostate tumors. findings for Cav-1 in human prostate and provide further for using animal model to the role of Cav-1 in prostate tumorigenesis. of Cav-1 the of at of of mice a prostate the of a tumor in TRAMP/Cav-1(-/-) mice was to tumor burden, prostate tumors were and The tumor mouse was for the and for the that the loss of Cav-1 prostate tumor in TRAMP mice. of one of in mice was also to in reductions in tumor a results with and were the and resulted in a significant in primary tumor Furthermore, of and mice tumors as as with of the TRAMP mice these results that or loss of Cav-1 is to prostate examination of the prostate tumors derived from WT, HET, or TRAMP mice revealed that tumors were mice that did not tumors, we their and of TRAMP mice at of revealed of prostate cancer, of prostatic intraepithelial and small of well or tissue in the and prostate T.M. W.J. 2003; PubMed Scopus Google Scholar). we found significant the of or TRAMP mice at of mice evidence of ranging from to transformed tissue in to the that the or loss of Cav-1 does not affect the in the of prostate cancer, rather progression to advanced invasive disease. of Cav-1 the of and Cav-1 has been in human metastatic prostate cancer and with the and G. T.M. Google Scholar, T. G. S. J. A. S. S. 2003; PubMed Scopus Google we also to the loss of Cav-1 the development of metastatic in TRAMP mice. we the of in regional lymph in of the TRAMP of gene a of and and for the is with in TRAMP mice that have reported of to lymph at J.R. R. Google Scholar). we found that or loss of Cav-1 resulted in decreases in the these in the regional lymph lymph mice of metastatic in with for mice and for TRAMP/Cav-1(-/-) mice. the and resulted in a significant in metastatic we also the of TRAMP mice for the development of distant metastatic with significantly than metastasis to regional lymph We found that the or loss of Cav-1 resulted in significantly levels of metastatic of at one as with of mice and of TRAMP/Cav-1(-/-) mice Furthermore, the of in and TRAMP/Cav-1(-/-) mice was significantly reduced from in mice to in and (-/-) mice were also in the and of mice or not in or (-/-) mice these results that TRAMP mice one or both alleles of Cav-1 to metastatic and that Cav-1 expression to a of advanced prostate of Cav-1 in of for was to the expression of the Cav-1 expression in prostate the in in mice and mice were of of Cav-1, as to of Cav-1 during prostate cell we prostate tissue from and mice and Cav-1 and of TRAMP mice not advanced tumors, TRAMP mice evidence of both and their prostate T.M. W.J. 2003; PubMed Scopus Google Scholar). in Cav-1 is expressed at levels in normal prostate and is a of Cav-1 levels with in TRAMP prostate an abundance of expression the of prostate the expression of has on the expression levels of Cav-1, suggesting that the of Cav-1 in of prostate tumor development an cellular these results also that of Cav-1 during prostate in a The TRAMP prostate shown in is with to PIN, and and and an increased of in the TRAMP model to well adenocarcinoma and to that the of Cav-1 does not in these of Cav-1 is a during the transformation of adenocarcinoma from a well to a we and on prostate tumors from TRAMP mice. loss of Cav-1 did not the expression of the as and has been that of Cav-1 results in an in expression in various B. J.A. Schubert W. F. R.G. M. Pestell R.G. Di Vizio D. Jr., B. G. W. Lisanti M.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). we also and Cav-1 on prostate tumors derived from mice. although expression is with tumors, is Cav-1 in the prostate carcinoma cells of tumors Cav-1 that these tumors reductions in Cav-1 levels than the from one Cav-1 findings that tumors have a Cav-1 expression to TRAMP/Cav-1(-/-) tumors and an as to prostate in and TRAMP/Cav-1(-/-) mice of Cav-1 in TRAMP with the role of Cav-1 in mouse prostate cancer cells with to we three prostate carcinoma cell lines derived from TRAMP prostate and three TRAMP cell lines and the their and prostate J.R. 1997; Google Scholar). We these cell lines for Cav-1 expression and found that levels of Cav-1, Cav-1 expressed Cav-1 levels were the various cell revealed that Cav-1 to the plasma in a for Cav-1 in and cells we these cell lines the of mice and the development of tumors. reported J.R. 1997; Google and cell lines form tumors, with cells in the tumors, cells not form tumors, and is to that tumor with Cav-1 expression in these cells, suggesting that the levels of Cav-1 the of these murine prostate cells to form tumors. of Cav-1 in the and the role of Cav-1 in in these cells, we Cav-1 in cells using an We also to Cav-1 in cells a recombinant to the expression of Cav-1 to tumor We cell lines a using the for the down-regulation of Cav-1 and the for recombinant Cav-1 of the cell lines was that Cav-1 levels in cells, as with or these cell lines were the of we found a in the and of tumors derived from cells of Cav-1 in cells was not to tumor findings that, although Cav-1 is not to tumors, Cav-1 expression levels the development of tumors a for down-regulation of Cav-1 in cells the ability of prostate carcinoma cells to form tumors. We also the down-regulation of Cav-1 in cells the ability of these cells to of and cells were the of mice the the of the loss of Cav-1 the ability of these prostate tumor cells to the and form metastatic tumors in an the were in and for derived from mice with cells an of metastatic a in the of metastatic with from mice with cells, an of metastatic from cells were significantly with results the findings from the transgenic mouse and that down-regulation of Cav-1 in prostate cells both the processes of and Moreover, the cellular provide evidence that the decreases in prostate and metastasis in and TRAMP mice of the loss of Cav-1 expression in prostate carcinoma of Cav-1 in of in TRAMP to the loss of Cav-1 results in prostate and we the processes of and apoptosis in the cell tumors, and TRAMP prostate tumors. We have that Cav-1 has a role in cellular in certain cell transformed fibroblasts and mammary cells T.M. F. J. Muller W.J. Chopra N.G. Pestell R.G. Lisanti M.P. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, T.M. Cheung M.W. Cohen A.W. Razani B. P. Pestell R.G. Lisanti M.P. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). we cell and on the cell in We found that the down-regulation of Cav-1 in cells resulted in a for growth in in with results that loss of Cav-1 a Despite for proliferating cell nuclear a well marker for cellular revealed significant in the of cells in or TRAMP prostate tumors on tumors derived from and cells also revealed significant We also the expression of and in TRAMP and tumors and found in the levels of these has been that, in prostate to an critical role during the of S. Rev. PubMed Scopus Google Scholar). Furthermore, a role for Cav-1 in prostate cancer cell has been in cell G. S. T. Y. J. Google Scholar, Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). we to a of apoptosis, in TRAMP prostate tumors and tumors derived from We found that loss of Cav-1 resulted in in the of TRAMP tumors, as with TRAMP tumors prostate tumors an of as with in TRAMP/Cav-1(-/-) tumors. was highly significant and that the of Cav-1 in prostate carcinoma cells has an To the function of Cav-1 is indeed a we also on tumors derived from prostate tumor we found that the loss of Cav-1 resulted in highly significant in the of apoptosis in tumors derived from cells these findings an role for Cav-1 in prostate carcinoma cells during prostate tumorigenesis. TRAMP/Cav-1(-/-) of PTEN and have implicated Cav-1 in cell in prostate cancer cells Mol. Cell. Biol. 2003; PubMed Scopus Google we TRAMP tumors for using a that at we did not significant in the levels of the tumors we in the levels of prostate apoptosis response factor-4 in TRAMP tumors is a prostate marker that both and prostate cancer cells to apoptosis when M. Google Scholar). Moreover, the well lipid tumor reduced levels in TRAMP tumors and PTEN is or in primary human prostate cancer, and its in mice results in metastatic prostate cancer S. J. J. G. P. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). has been shown that Cav-1 with suggesting that these in vivo G. T.M. Google Scholar). the increased and PTEN expression in TRAMP tumors Cav-1 expression further molecular evidence that these Cav-1 tumors indeed to apoptosis to tumor and metastasis of the primary of cancer research is to genetic that to and to the a gene or tumor for their as for cancer progression or as for The Cav-1 gene has of its expression patterns in human its down-regulation in and mammary and its in and prostate cancer is the of in in the that as of or for is critical in and and is an between Cav-1 protein levels and prostate cancer Cav-1 expression to with higher prostate carcinoma and a in G. T.M. Google Scholar, T. G. S. J. A. S. S. 2003; PubMed Scopus Google Scholar). have molecular genetic of a between Cav-1 expression and prostate is Full of prostate tumor development using a transgenic mouse model to such indeed in our current results the first molecular genetic evidence that Cav-1 prostate in vivo. of derived from and TRAMP mice revealed that Cav-1 is expressed at levels in and transformed prostate Cav-1 was in the of prostate adenocarcinoma TRAMP tumors significant Cav-1 More we showed that loss of Cav-1 prostate cancer development significantly both primary tumor and metastatic in a transgenic prostate cancer or loss of Cav-1 is to both of these of advanced The that prostate tumors reduced Cav-1 levels at a for prostate in TRAMP mice to TRAMP mice. Furthermore, we have that these results of the loss of Cav-1 prostate carcinoma cells, as down-regulation of Cav-1 in a mouse prostate carcinoma cell tumor and We have also evidence to cell that Cav-1 has in prostate cancer, as both TRAMP prostate tumors and cell tumors Cav-1 expression increased of these results a between Cav-1 expression and the development of advanced prostate with to primary tumor and metastatic disease. Our findings also the of Cav-1 as a marker for prostate cancer progression and identified Cav-1 as a for or gene these results with our in mammary that loss of Cav-1 mammary and metastasis a transgenic model (9Williams T.M. Cheung M.W. Park D.S. Razani B. Cohen A.W. Muller W.J. Di Vizio D. Chopra N.G. Pestell R.G. Lisanti M.P. Mol. Biol. Cell. 2003; 14: 1027-1042Crossref PubMed Scopus (135) Google Scholar, T.M. F. J. Muller W.J. Chopra N.G. Pestell R.G. Lisanti M.P. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). that Cav-1 expression inhibits mammary tumor growth and metastasis Oncogene. 2004; PubMed Scopus Google Scholar). these mammary carcinoma Cav-1 to have a genetic of Cav-1 results in and were in or expression between and Cav-1 TRAMP prostate tumors these data that Cav-1 has tissue or cell with to in transformed mammary in transformed prostate in with provide evidence that Cav-1 to provide a to transformed cells in certain human Cav-1 down-regulation may also cancer development in a of mammary of the molecular for Cav-1 functions as a or in and was the of the TRAMP animal model for prostate has been in of the TRAMP was that a of prostate tumors in TRAMP mice derived from cells and not from the prostate was on the of several such as in advanced TRAMP prostate tumors. and T.M. W.J. 2003; PubMed Scopus Google have evidence that is not the have that the in TRAMP tumors as in and prostatic carcinoma TRAMP the of does not that transformed cells have cells, as and also that the majority of these cells also the a protein not expressed cells of the of the of a in of human prostatic further the progression of the human prostatic and the of the TRAMP model for prostate carcinoma progression T.M. W.J. 2003; PubMed Scopus Google Scholar). we showed that Cav-1 protein expression levels indeed in TRAMP prostate tumors, with the of Cav-1 in human prostate G. T.M. Google Scholar, T. G. S. J. A. S. S. 2003; PubMed Scopus Google Scholar). our current results with Cav-1 further the of the TRAMP model in the of prostate in vivo. We R. for tissue and