Caveolin-1 P132L Mutation in Human Cancers: 1 CAVeat to be Voiced

Abstract

This Commentary discusses the role of caveolin-1 in human cancer. This Commentary discusses the role of caveolin-1 in human cancer. Caveolae are 50–100 nm flask-shaped invaginations of the plasma membrane that function as membrane organizing centers and play important roles in intracellular trafficking of cellular components (eg, lipid and cholesterol) and signal transduction.1Carver LA Schnitzer JE Caveolae: mining little caves for new cancer targets.Nat Rev Cancer. 2003; 3: 571-581Crossref PubMed Scopus (228) Google Scholar The CAV1 gene maps to 7q31.1 and encodes the ubiquitously expressed caveolin-1, which is an essential component of caveolae. Caveolin-1 is believed to regulate the activity of a plethora of signaling molecules highly represented in caveolae, such as H-ras, c-src, and src-like kinases; endothelial nitric oxide synthase; G-proteins and membrane-associated receptors coupled to G-proteins; or tyrosine kinase receptors including epidermal growth factor receptor.1Carver LA Schnitzer JE Caveolae: mining little caves for new cancer targets.Nat Rev Cancer. 2003; 3: 571-581Crossref PubMed Scopus (228) Google Scholar In normal breast tissue, caveolin-1 is expressed at high levels in adipocytes, endothelial cells, fibroblasts, and myoepithelial cells of the breast.1Carver LA Schnitzer JE Caveolae: mining little caves for new cancer targets.Nat Rev Cancer. 2003; 3: 571-581Crossref PubMed Scopus (228) Google Scholar Initial studies have suggested that caveolin-1 would have properties consistent with those of a tumor suppressor protein.2Hayashi K Matsuda S Machida K Yamamoto T Fukuda Y Nimura Y Hayakawa T Hamaguchi M Invasion activating caveolin-1 mutation in human scirrhous breast cancers.Cancer Res. 2001; 61: 2361-2364PubMed Google Scholar3Lee H Park DS Razani B Russell RG Pestell RG Lisanti MP Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia.Am J Pathol. 2002; 161: 1357-1369Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar4Li T Sotgia F Vuolo MA Li M Yang WC Pestell RG Sparano JA Lisanti MP Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status.Am J Pathol. 2006; 168: 1998-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar A dominant negative mutation of the CAV1 gene was reported to be found in up to 20% of estrogen receptor (ER)-positive breast cancers.2Hayashi K Matsuda S Machida K Yamamoto T Fukuda Y Nimura Y Hayakawa T Hamaguchi M Invasion activating caveolin-1 mutation in human scirrhous breast cancers.Cancer Res. 2001; 61: 2361-2364PubMed Google Scholar4Li T Sotgia F Vuolo MA Li M Yang WC Pestell RG Sparano JA Lisanti MP Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status.Am J Pathol. 2006; 168: 1998-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Surprisingly, however, CAV1 knock-out mice failed to develop any tumor.1Carver LA Schnitzer JE Caveolae: mining little caves for new cancer targets.Nat Rev Cancer. 2003; 3: 571-581Crossref PubMed Scopus (228) Google Scholar3Lee H Park DS Razani B Russell RG Pestell RG Lisanti MP Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia.Am J Pathol. 2002; 161: 1357-1369Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Furthermore, the presence of CAV1 gene mutations could not be independently validated.5Chen ST Lin SY Yeh KT Kuo SJ Chan WL Chu YP Chang JG Mutational, epigenetic and expressional analyses of caveolin-1 gene in breast cancers.Int J Mol Med. 2004; 14: 577-582PubMed Google Scholar6Heighway J Knapp T Boyce L Brennand S Field JK Betticher DC Ratschiller D Gugger M Donovan M Lasek A Rickert P Expression profiling of primary non-small cell lung cancer for target identification.Oncogene. 2002; 21: 7749-7763Crossref PubMed Scopus (141) Google Scholar7Ho CC Huang PH Huang HY Chen YH Yang PC Hsu SM Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation.Am J Pathol. 2002; 161: 1647-1656Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar8Hurlstone AF Reid G Reeves JR Fraser J Strathdee G Rahilly M Parkinson EK Black DM Analysis of the CAVEOLIN-1 gene at human chromosome 7q31.1 in primary tumours and tumour-derived cell lines.Oncogene. 1999; 18: 1881-1890Crossref PubMed Scopus (120) Google Scholar9Sunaga N Miyajima K Suzuki M Sato M White MA Ramirez RD Shay JW Gazdar AF Minna JD Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer.Cancer Res. 2004; 64: 4277-4285Crossref PubMed Scopus (166) Google Scholar Concurrent with the controversies about the role of CAV1 as a tumor suppressor gene, evidence of caveolin-1 as a potential oncogene has been mounting.7Ho CC Huang PH Huang HY Chen YH Yang PC Hsu SM Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation.Am J Pathol. 2002; 161: 1647-1656Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar8Hurlstone AF Reid G Reeves JR Fraser J Strathdee G Rahilly M Parkinson EK Black DM Analysis of the CAVEOLIN-1 gene at human chromosome 7q31.1 in primary tumours and tumour-derived cell lines.Oncogene. 1999; 18: 1881-1890Crossref PubMed Scopus (120) Google Scholar9Sunaga N Miyajima K Suzuki M Sato M White MA Ramirez RD Shay JW Gazdar AF Minna JD Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer.Cancer Res. 2004; 64: 4277-4285Crossref PubMed Scopus (166) Google Scholar10Elsheikh SE Green AR Rakha EA Samaka RM Ammar AA Powe D Reis-Filho JS Ellis IO Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype.Br J Cancer. 2008; 99: 327-334Crossref PubMed Scopus (122) Google Scholar11Joshi B Strugnell SS Goetz JG Kojic LD Cox ME Griffith OL Chan SK Jones SJ Leung SP Masoudi H Leung S Wiseman SM Nabi IR Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion.Cancer Res. 2008; 68: 8210-8220Crossref PubMed Scopus (211) Google Scholar12Liedtke C Kersting C Burger H Kiesel L Wulfing P Caveolin-1 expression in benign and malignant lesions of the breast.World J Surg Oncol. 2007; 5: 110Crossref PubMed Scopus (28) Google Scholar13Pinilla SM Honrado E Hardisson D Benitez J Palacios J Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer.Breast Cancer Res Treat. 2006; 99: 85-90Crossref PubMed Scopus (118) Google Scholar14Savage K Lambros MB Robertson D Jones RL Jones C Mackay A James M Hornick JL Pereira EM Milanezi F Fletcher CD Schmitt FC Ashworth A Reis-Filho JS Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis.Clin Cancer Res. 2007; 13: 90-101Crossref PubMed Scopus (188) Google Scholar15Van den Eynden GG Van Laere SJ Van der Auwera I Merajver SD Van Marck EA van Dam P Vermeulen PB Dirix LY van Golen KL Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer.Breast Cancer Res Treat. 2006; 95: 219-228Crossref PubMed Scopus (77) Google Scholar In fact, multiple independent groups have reported overexpression of caveolin-1 in aggressive subtypes of cancer,10Elsheikh SE Green AR Rakha EA Samaka RM Ammar AA Powe D Reis-Filho JS Ellis IO Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype.Br J Cancer. 2008; 99: 327-334Crossref PubMed Scopus (122) Google Scholar11Joshi B Strugnell SS Goetz JG Kojic LD Cox ME Griffith OL Chan SK Jones SJ Leung SP Masoudi H Leung S Wiseman SM Nabi IR Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion.Cancer Res. 2008; 68: 8210-8220Crossref PubMed Scopus (211) Google Scholar13Pinilla SM Honrado E Hardisson D Benitez J Palacios J Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer.Breast Cancer Res Treat. 2006; 99: 85-90Crossref PubMed Scopus (118) Google Scholar14Savage K Lambros MB Robertson D Jones RL Jones C Mackay A James M Hornick JL Pereira EM Milanezi F Fletcher CD Schmitt FC Ashworth A Reis-Filho JS Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis.Clin Cancer Res. 2007; 13: 90-101Crossref PubMed Scopus (188) Google Scholar15Van den Eynden GG Van Laere SJ Van der Auwera I Merajver SD Van Marck EA van Dam P Vermeulen PB Dirix LY van Golen KL Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer.Breast Cancer Res Treat. 2006; 95: 219-228Crossref PubMed Scopus (77) Google Scholar and even CAV1 gene amplification has been documented,14Savage K Lambros MB Robertson D Jones RL Jones C Mackay A James M Hornick JL Pereira EM Milanezi F Fletcher CD Schmitt FC Ashworth A Reis-Filho JS Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis.Clin Cancer Res. 2007; 13: 90-101Crossref PubMed Scopus (188) Google Scholar16Han SY Druck T Huebner K Candidate tumor suppressor genes at FRA7G are coamplified with MET and do not suppress malignancy in a gastric cancer.Genomics. 2003; 81: 105-107Crossref PubMed Scopus (22) Google Scholar although this has been shown to be a rare phenomenon. Furthermore, expression of caveolin-1 in stromal cells of breast cancer has also been shown to be associated with the outcome of breast cancer patients.17Sloan EK Ciocca DR Pouliot N Natoli A Restall C Henderson MA Fanelli MA Cuello-Carrion FD Gago FE Anderson RL Stromal cell expression of caveolin-1 predicts outcome in breast cancer.Am J Pathol. 2009; 174: 2035-2043Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar18Witkiewicz AK Dasgupta A Nguyen KH Liu C Kovatich AJ Schwartz GF Pestell RG Sotgia F Rui H Lisanti MP Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer.Cancer Biol Ther. 2009; 8: 1071-1079Crossref PubMed Scopus (114) Google Scholar Despite the interest in the tumor suppressive and oncogenic functions of caveolin-1, numerous issues remain unanswered. For instance, caveolin-1 expression in normal luminal epithelial cells of normal breast lobules and ducts remains a matter of controversy, as does the existence and prevalence of the CAV1 P132L dominant-negative mutation. In this issue of The Journal of Molecular Diagnostics, Koike et al19Koike S Kodera Y Nakao A Iwata H Yatabe Y Absence of the caveolin-1 P132L mutation in cancers of the breast and other organs.J Mol Diagn. 2010; 12: 712-717Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar have addressed the question of the prevalence of the CAV1 P132L mutation in human cancer. Using three different methods for mutation detection (ie, reverse-transcriptase direct sequencing, DNA-based direct sequencing, and cycleave PCR assay), the authors failed to detect the CAV1 P132L mutation in a large series of 409 human tumors, including 139 breast cancers [114 estrogen receptor (ER)-positive and 25 ER-negative tumors] and 270 cancers from other anatomical sites (ie, gastrointestinal tract, lung, ovary, and pancreas). Taken together, the findings reported by Koike et al19Koike S Kodera Y Nakao A Iwata H Yatabe Y Absence of the caveolin-1 P132L mutation in cancers of the breast and other organs.J Mol Diagn. 2010; 12: 712-717Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar and those by others5Chen ST Lin SY Yeh KT Kuo SJ Chan WL Chu YP Chang JG Mutational, epigenetic and expressional analyses of caveolin-1 gene in breast cancers.Int J Mol Med. 2004; 14: 577-582PubMed Google Scholar6Heighway J Knapp T Boyce L Brennand S Field JK Betticher DC Ratschiller D Gugger M Donovan M Lasek A Rickert P Expression profiling of primary non-small cell lung cancer for target identification.Oncogene. 2002; 21: 7749-7763Crossref PubMed Scopus (141) Google Scholar7Ho CC Huang PH Huang HY Chen YH Yang PC Hsu SM Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation.Am J Pathol. 2002; 161: 1647-1656Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar8Hurlstone AF Reid G Reeves JR Fraser J Strathdee G Rahilly M Parkinson EK Black DM Analysis of the CAVEOLIN-1 gene at human chromosome 7q31.1 in primary tumours and tumour-derived cell lines.Oncogene. 1999; 18: 1881-1890Crossref PubMed Scopus (120) Google Scholar9Sunaga N Miyajima K Suzuki M Sato M White MA Ramirez RD Shay JW Gazdar AF Minna JD Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer.Cancer Res. 2004; 64: 4277-4285Crossref PubMed Scopus (166) Google Scholar call into question the presence of the CAV1 P132L mutation in breast cancers and other cancer types and heat up the debate about the roles of caveolin-1 in human cancer. Since its first description in 1989, CAV1 has been the subject of extensive research; however, its role in cancer still remains a matter of controversy. Several lines of evidence3Lee H Park DS Razani B Russell RG Pestell RG Lisanti MP Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia.Am J Pathol. 2002; 161: 1357-1369Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar4Li T Sotgia F Vuolo MA Li M Yang WC Pestell RG Sparano JA Lisanti MP Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status.Am J Pathol. 2006; 168: 1998-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar20Mercier I Bryant KG Sotgia F Bonuccelli G Witkiewicz AK Dasgupta A Jasmin JF Pestell RG Lisanti MP Using Caveolin-1 epithelial immunostaining patterns to stratify human breast cancer patients and predict the Caveolin-1 (P132L) mutation.Cell Cycle. 2009; 8: 1396-1401Crossref PubMed Scopus (14) Google Scholar suggest that caveolin-1 may have tumor suppressor properties and that its down-regulation plays a role in breast cancer tumorigenesis. This assumption was also based on the high frequency of deletions of 7q31 (a fragile site known as FRA7G next to the CAV1 locus8Hurlstone AF Reid G Reeves JR Fraser J Strathdee G Rahilly M Parkinson EK Black DM Analysis of the CAVEOLIN-1 gene at human chromosome 7q31.1 in primary tumours and tumour-derived cell lines.Oncogene. 1999; 18: 1881-1890Crossref PubMed Scopus (120) Google Scholar) in human cancer,1Carver LA Schnitzer JE Caveolae: mining little caves for new cancer targets.Nat Rev Cancer. 2003; 3: 571-581Crossref PubMed Scopus (228) Google Scholar a high prevalence of an inactivating CAV1 mutation in breast cancer,2Hayashi K Matsuda S Machida K Yamamoto T Fukuda Y Nimura Y Hayakawa T Hamaguchi M Invasion activating caveolin-1 mutation in human scirrhous breast cancers.Cancer Res. 2001; 61: 2361-2364PubMed Google Scholar4Li T Sotgia F Vuolo MA Li M Yang WC Pestell RG Sparano JA Lisanti MP Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status.Am J Pathol. 2006; 168: 1998-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar and down-regulation of caveolin-1 in cancer cell lines, possibly due to CAV1 gene promoter hypermethylation.5Chen ST Lin SY Yeh KT Kuo SJ Chan WL Chu YP Chang JG Mutational, epigenetic and expressional analyses of caveolin-1 gene in breast cancers.Int J Mol Med. 2004; 14: 577-582PubMed Google Scholar9Sunaga N Miyajima K Suzuki M Sato M White MA Ramirez RD Shay JW Gazdar AF Minna JD Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer.Cancer Res. 2004; 64: 4277-4285Crossref PubMed Scopus (166) Google Scholar A potential genetic basis for caveolin-1 inactivation in a subgroup of breast cancer stemmed from the study by Hayashi et al,2Hayashi K Matsuda S Machida K Yamamoto T Fukuda Y Nimura Y Hayakawa T Hamaguchi M Invasion activating caveolin-1 mutation in human scirrhous breast cancers.Cancer Res. 2001; 61: 2361-2364PubMed Google Scholar who described a somatic point mutation of CAV1 gene at codon 132 (P132L). This mutation was reported to cause abrogation of caveolin-1 function due to its dominant negative properties2Hayashi K Matsuda S Machida K Yamamoto T Fukuda Y Nimura Y Hayakawa T Hamaguchi M Invasion activating caveolin-1 mutation in human scirrhous breast cancers.Cancer Res. 2001; 61: 2361-2364PubMed Google Scholar3Lee H Park DS Razani B Russell RG Pestell RG Lisanti MP Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia.Am J Pathol. 2002; 161: 1357-1369Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar and to lead to activation of mitogen-activated protein kinase signaling pathway. This mutation was found in 16% of 92 samples of human breast cancers, mainly in ‘scirrhous’ carcinomas (ie, the equivalent of a subtype of invasive ductal carcinoma of no special type in the Japanese classification of breast cancer).2Hayashi K Matsuda S Machida K Yamamoto T Fukuda Y Nimura Y Hayakawa T Hamaguchi M Invasion activating caveolin-1 mutation in human scirrhous breast cancers.Cancer Res. 2001; 61: 2361-2364PubMed Google Scholar Five years later, the CAV1 P132L mutation was found in one study to be present in 9% (n = 5/55) of breast cancers.4Li T Sotgia F Vuolo MA Li M Yang WC Pestell RG Sparano JA Lisanti MP Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status.Am J Pathol. 2006; 168: 1998-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Interestingly, however, six novel CAV1 mutations were described and together with CAV1 P132L mutation were shown to be restricted to ER-positive cancers, suggesting that the CAV1 gene is mutated in up to 35% of ER-positive breast carcinomas.4Li T Sotgia F Vuolo MA Li M Yang WC Pestell RG Sparano JA Lisanti MP Caveolin-1 mutations in human breast cancer: functional association with estrogen receptor alpha-positive status.Am J Pathol. 2006; 168: 1998-2013Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Further characterization of the functional properties of the P132L mutation was performed using in vitro models.2Hayashi K Matsuda S Machida K Yamamoto T Fukuda Y Nimura Y Hayakawa T Hamaguchi M Invasion activating caveolin-1 mutation in human scirrhous breast cancers.Cancer Res. 2001; 61: 2361-2364PubMed Google Scholar3Lee H Park DS Razani B Russell RG Pestell RG Lisanti MP Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia.Am J Pathol. 2002; 161: 1357-1369Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Surprisingly, however, several groups have now failed to independently confirm the presence of these mutations of the CAV1 gene in human cancer samples and cancer cell lines.5Chen ST Lin SY Yeh KT Kuo SJ Chan WL Chu YP Chang JG Mutational, epigenetic and expressional analyses of caveolin-1 gene in breast cancers.Int J Mol Med. 2004; 14: 577-582PubMed Google Scholar6Heighway J Knapp T Boyce L Brennand S Field JK Betticher DC Ratschiller D Gugger M Donovan M Lasek A Rickert P Expression profiling of primary non-small cell lung cancer for target identification.Oncogene. 2002; 21: 7749-7763Crossref PubMed Scopus (141) Google Scholar7Ho CC Huang PH Huang HY Chen YH Yang PC Hsu SM Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation.Am J Pathol. 2002; 161: 1647-1656Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar8Hurlstone AF Reid G Reeves JR Fraser J Strathdee G Rahilly M Parkinson EK Black DM Analysis of the CAVEOLIN-1 gene at human chromosome 7q31.1 in primary tumours and tumour-derived cell lines.Oncogene. 1999; 18: 1881-1890Crossref PubMed Scopus (120) Google Scholar9Sunaga N Miyajima K Suzuki M Sato M White MA Ramirez RD Shay JW Gazdar AF Minna JD Different roles for caveolin-1 in the development of non-small cell lung cancer versus small cell lung cancer.Cancer Res. 2004; 64: 4277-4285Crossref PubMed Scopus (166) Google Scholar19Koike S Kodera Y Nakao A Iwata H Yatabe Y Absence of the caveolin-1 P132L mutation in cancers of the breast and other organs.J Mol Diagn. 2010; 12: 712-717Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Supporting their assumption of CAV1 being a tumor suppressor gene, the same group has characterized an in vivo model of CAV1 (−/−) null mice, which developed “wide-spread mammary epithelial cell hyperplasia (a pre-malignant mammary lesion).”3Lee H Park DS Razani B Russell RG Pestell RG Lisanti MP Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia.Am J Pathol. 2002; 161: 1357-1369Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar It should be noted, however, that CAV1 null mice failed to develop mammary tumors, even at up to 9 months of age. Furthermore, the degree of epithelial cell hyperplasia illustrated in that study (Figures 7–9)3Lee H Park DS Razani B Russell RG Pestell RG Lisanti MP Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia.Am J Pathol. 2002; 161: 1357-1369Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar would perhaps be considered ‘mild’ if human breast pathology criteria were adopted. Furthermore, the other alterations observed in those mice,3Lee H Park DS Razani B Russell RG Pestell RG Lisanti MP Caveolin-1 mutations (P132L and null) and the pathogenesis of breast cancer: caveolin-1 (P132L) behaves in a dominant-negative manner and caveolin-1 (-/-) null mice show mammary epithelial cell hyperplasia.Am J Pathol. 2002; 161: 1357-1369Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar such as fibrosis and pronounced lobular development, have not been shown to be associated with cancer development. Importantly, depending on the antibody used,8Hurlstone AF Reid G Reeves JR Fraser J Strathdee G Rahilly M Parkinson EK Black DM Analysis of the CAVEOLIN-1 gene at human chromosome 7q31.1 in primary tumours and tumour-derived cell lines.Oncogene. 1999; 18: 1881-1890Crossref PubMed Scopus (120) Google Scholar10Elsheikh SE Green AR Rakha EA Samaka RM Ammar AA Powe D Reis-Filho JS Ellis IO Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype.Br J Cancer. 2008; 99: 327-334Crossref PubMed Scopus (122) Google Scholar13Pinilla SM Honrado E Hardisson D Benitez J Palacios J Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer.Breast Cancer Res Treat. 2006; 99: 85-90Crossref PubMed Scopus (118) Google Scholar14Savage K Lambros MB Robertson D Jones RL Jones C Mackay A James M Hornick JL Pereira EM Milanezi F Fletcher CD Schmitt FC Ashworth A Reis-Filho JS Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis.Clin Cancer Res. 2007; 13: 90-101Crossref PubMed Scopus (188) Google Scholar caveolin-1 protein is not expressed at detectable levels in luminal epithelial cells of the normal breast; this fact may not be trivially reconciled with the potential tumor suppressor function of caveolin-1 in luminal breast cancer. There has been increasingly more coherent data to suggest that caveolin-1 may also have oncogenic properties in human cancer. It has been demonstrated that breast cancer cell lines, in particular those displaying more overt invasive properties as defined by invasion assays (eg, MDA-MB-231, BT549, Hs578T), harbor high levels of caveolin-1 expression at the mRNA and protein levels.11Joshi B Strugnell SS Goetz JG Kojic LD Cox ME Griffith OL Chan SK Jones SJ Leung SP Masoudi H Leung S Wiseman SM Nabi IR Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion.Cancer Res. 2008; 68: 8210-8220Crossref PubMed Scopus (211) Google Scholar21Yamaguchi H Takeo Y Yoshida S Kouchi Z Nakamura Y Fukami K Lipid rafts and caveolin-1 are required for invadopodia formation and extracellular matrix degradation by human breast cancer cells.Cancer Res. 2009; 69: 8594-8602Crossref PubMed Scopus (144) Google Scholar Several studies provided mechanistic evidence of the potential oncogenic properties of caveolin-1.11Joshi B Strugnell SS Goetz JG Kojic LD Cox ME Griffith OL Chan SK Jones SJ Leung SP Masoudi H Leung S Wiseman SM Nabi IR Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion.Cancer Res. 2008; 68: 8210-8220Crossref PubMed Scopus (211) Google Scholar15Van den Eynden GG Van Laere SJ Van der Auwera I Merajver SD Van Marck EA van Dam P Vermeulen PB Dirix LY van Golen KL Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer.Breast Cancer Res Treat. 2006; 95: 219-228Crossref PubMed Scopus (77) Google Scholar21Yamaguchi H Takeo Y Yoshida S Kouchi Z Nakamura Y Fukami K Lipid rafts and caveolin-1 are required for invadopodia formation and extracellular matrix degradation by human breast cancer cells.Cancer Res. 2009; 69: 8594-8602Crossref PubMed Scopus (144) Google Scholar For instance, the interaction between caveolin-1 and membrane type 1 matrix metalloproteinase, which colocalize at the subcellular compartment, seems to be an essential regulator of matrix degradation and cancer cell invasion.21Yamaguchi H Takeo Y Yoshida S Kouchi Z Nakamura Y Fukami K Lipid rafts and caveolin-1 are required for invadopodia formation and extracellular matrix degradation by human breast cancer cells.Cancer Res. 2009; 69: 8594-8602Crossref PubMed Scopus (144) Google Scholar Moreover, two independent groups described activation of Rho/ROCK signaling by caveolin-1.11Joshi B Strugnell SS Goetz JG Kojic LD Cox ME Griffith OL Chan SK Jones SJ Leung SP Masoudi H Leung S Wiseman SM Nabi IR Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion.Cancer Res. 2008; 68: 8210-8220Crossref PubMed Scopus (211) Google Scholar15Van den Eynden GG Van Laere SJ Van der Auwera I Merajver SD Van Marck EA van Dam P Vermeulen PB Dirix LY van Golen KL Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer.Breast Cancer Res Treat. 2006; 95: 219-228Crossref PubMed Scopus (77) Google Scholar Accordingly, numerous studies have shown caveolin-1 overexpression in human cancer samples, including breast,8Hurlstone AF Reid G Reeves JR Fraser J Strathdee G Rahilly M Parkinson EK Black DM Analysis of the CAVEOLIN-1 gene at human chromosome 7q31.1 in primary tumours and tumour-derived cell lines.Oncogene. 1999; 18: 1881-1890Crossref PubMed Scopus (120) Google Scholar10Elsheikh SE Green AR Rakha EA Samaka RM Ammar AA Powe D Reis-Filho JS Ellis IO Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype.Br J Cancer. 2008; 99: 327-334Crossref PubMed Scopus (122) Google Scholar11Joshi B Strugnell SS Goetz JG Kojic LD Cox ME Griffith OL Chan SK Jones SJ Leung SP Masoudi H Leung S Wiseman SM Nabi IR Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion.Cancer Res. 2008; 68: 8210-8220Crossref PubMed Scopus (211) Google Scholar13Pinilla SM Honrado E Hardisson D Benitez J Palacios J Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer.Breast Cancer Res Treat. 2006; 99: 85-90Crossref PubMed Scopus (118) Google Scholar14Savage K Lambros MB Robertson D Jones RL Jones C Mackay A James M Hornick JL Pereira EM Milanezi F Fletcher CD Schmitt FC Ashworth A Reis-Filho JS Caveolin 1 is overexpressed and amplified in a subset of basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, immunohistochemical, and in situ hybridization analysis.Clin Cancer Res. 2007; 13: 90-101Crossref PubMed Scopus (188) Google Scholar15Van den Eynden GG Van Laere SJ Van der Auwera I Merajver SD Van Marck EA van Dam P Vermeulen PB Dirix LY van Golen KL Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer.Breast Cancer Res Treat. 2006; 95: 219-228Crossref PubMed Scopus (77) Google Scholar colorectal,11Joshi B Strugnell SS Goetz JG Kojic LD Cox ME Griffith OL Chan SK Jones SJ Leung SP Masoudi H Leung S Wiseman SM Nabi IR Phosphorylated caveolin-1 regulates Rho/ROCK-dependen