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• W76295024 abstract "This Commentary highlights two articles in this issue of the American Journal of Pathology, discussing the implications of stromal expression of caveolin-1 in breast cancer. This Commentary highlights two articles in this issue of the American Journal of Pathology, discussing the implications of stromal expression of caveolin-1 in breast cancer. Need it be said again that no cell is an island, and in tissue-specificity and cancer, context is supreme.Decades ago, seminal recombination experiments illustrated the dominant role of mammary mesenchyme in directing epithelial development1Cunha GR Young P Christov K Guzman R Nandi S Talamantes F Thordarson G Mammary phenotypic expression induced in epidermal cells by embryonic mammary mesenchyme.Acta Anat (Basel). 1995; 152: 195-204Crossref PubMed Scopus (71) Google Scholar, 2Propper A Gomot L Control of chick epidermis differentiation by rabbit mammary mesenchyme.Experientia. 1973; 29: 1543-1544Crossref PubMed Scopus (25) Google Scholar, 3Sakakura T Nishizuka Y Dawe CJ Mesenchyme-dependent morphogenesis and epithelium-specific cytodifferentiation in mouse mammary gland.Science. 1976; 194: 1439-1441Crossref PubMed Scopus (254) Google Scholar and strongly suggested that the microenvironment also plays a significant role in the manifestation of carcinoma. More direct evidence for such functions came from a study demonstrating that an unadulterated microenvironment can suppress the malignant phenotype and re-direct tumor cells to give rise to normally functioning tissues and, indeed, healthy mice.4Mintz B Illmensee K Normal genetically mosaic mice produced from malignant teratocarcinoma cells.Proc Natl Acad Sci USA. 1975; 72: 3585-3589Crossref PubMed Scopus (897) Google Scholar One may wonder why such a stunning finding did not convince the scientific community to pay more attention to the role of context. The answers are complex; however, concomitantly with this finding, the roles of oncogenes and mutations were being discovered. That excitement carried the day, especially because no one subsequently determined whether or not these mice generated from malignant cells contained tumorigenic mutations, and no new group reproduced the work. The following decade saw the discovery that even potent oncogenes could be ruled by context,5Dolberg DS Bissell MJ Inability of Rous sarcoma virus to cause sarcomas in the avian embryo.Nature. 1984; 309: 552-556Crossref PubMed Scopus (147) Google Scholar and recently it was shown that similar reprogramming of metastatic melanoma by an embryonic microenvironment was possible.6Kulesa PM Kasemeier-Kulesa JC Teddy JM Margaryan NV Seftor EA Seftor RE Hendrix MJ Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment.Proc Natl Acad Sci USA. 2006; 103: 3752-3757Crossref PubMed Scopus (189) Google Scholar There are many more examples that are not as clear cut, but are nevertheless compelling. The extensive literature of two-stage carcinogenesis, namely initiation and progression, indeed clearly indicates that “initiation” and DNA damage alone are not sufficient to allow carcinogenesis. These findings imply that ‘once a tumor or an oncogene, not always a tumor or an oncogene.’A renewed focus on the tumor microenvironment as a therapeutic target7Bissell MJ Radisky D Putting tumours in context.Nat Rev Cancer. 2001; 1: 46-54Crossref PubMed Scopus (1710) Google Scholar has also led to the recognition that markers within the microenvironment could have predictive power. Two recently published reports identifying ‘stromal signatures’ in breast cancer patients prognostic for patient survival8Finak G Bertos N Pepin F Sadekova S Souleimanova M Zhao H Chen H Omeroglu G Meterissian S Omeroglu A Hallett M Park M Stromal gene expression predicts clinical outcome in breast cancer.Nat Med. 2008; 14: 518-527Crossref PubMed Scopus (1264) Google Scholar and predictive of response to chemotherapeutic treatment9Farmer P Bonnefoi H Anderle P Cameron D Wirapati P Becette V Andre S Piccart M Campone M Brain E Macgrogan G Petit T Jassem J Bibeau F Blot E Bogaerts J Aguet M Bergh J Iggo R Delorenzi M A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer.Nat Med. 2009; 15: 68-74Crossref PubMed Scopus (479) Google Scholar provide proof of this concept. In the current issue of The American Journal of Pathology, two independent studies10Sloan 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.The Am J Pathol. 2009; 174: 2035-2043Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 11Witkiewicz AK Dasgupta A Sotgia F Mercier I Pestell RG Sabel M Kleer CG Brody JR Lisanti MP An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.Am J Pathol. 2009; 174: 2023-2034Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar identify a novel stromal marker, caveolin (Cav)-1, which predicts clinical outcome of breast cancer patients irrespective of its expression in tumor epithelium.Cav-1 is a scaffolding protein essential to the structure of caveolae, “little caves” or invaginations in cellular plasma membranes.12Hnasko R Lisanti MP The biology of caveolae: lessons from caveolin knockout mice and implications for human disease.Mol Interv. 2003; 3: 445-464Crossref PubMed Scopus (172) Google Scholar Cav-1 recruits and arranges lipids and proteins to these membrane sites to function in endocytosis and signal transduction.12Hnasko R Lisanti MP The biology of caveolae: lessons from caveolin knockout mice and implications for human disease.Mol Interv. 2003; 3: 445-464Crossref PubMed Scopus (172) Google Scholar The observation that Cav-1 expression is attenuated in oncogenically transformed cells13Koleske AJ Baltimore D Lisanti MP Reduction of caveolin and caveolae in oncogenically transformed cells.Proc Natl Acad Sci USA. 1995; 92: 1381-1385Crossref PubMed Scopus (470) Google Scholar led to exploration of whether Cav-1 loss in mammary epithelium was causative. Although mechanistic data suggested that Cav-1 null mice exhibited aberrant epithelial growth,14Williams TM Sotgia F Lee H Hassan G Di Vizio D Bonuccelli G Capozza F Mercier I Rui H Pestell RG Lisanti MP Stromal and epithelial caveolin-1 both confer a protective effect against mammary hyperplasia and tumorigenesis: caveolin-1 antagonizes cyclin D1 function in mammary epithelial cells.Am J Pathol. 2006; 169: 1784-1801Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar and that forcing Cav-1 expression in breast cancer cell lines inhibited growth and metastases in xenograft models,15Sloan EK Stanley KL Anderson RL Caveolin-1 inhibits breast cancer growth and metastasis.Oncogene. 2004; 23: 7893-7897Crossref PubMed Scopus (138) Google Scholar a clinical link proved elusive. However, MMTV-PyMT tumors transplanted into the fat pads of Cav-1 knockout mice displayed significantly enhanced growth (vs. wild-type mice),14Williams TM Sotgia F Lee H Hassan G Di Vizio D Bonuccelli G Capozza F Mercier I Rui H Pestell RG Lisanti MP Stromal and epithelial caveolin-1 both confer a protective effect against mammary hyperplasia and tumorigenesis: caveolin-1 antagonizes cyclin D1 function in mammary epithelial cells.Am J Pathol. 2006; 169: 1784-1801Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar motivating investigation of whether stromal Cav-1 expression correlates with human breast cancer patient survival.This is precisely what Witkiewicz et al,11Witkiewicz AK Dasgupta A Sotgia F Mercier I Pestell RG Sabel M Kleer CG Brody JR Lisanti MP An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.Am J Pathol. 2009; 174: 2023-2034Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar and Sloan et al,10Sloan 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.The Am J Pathol. 2009; 174: 2035-2043Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar demonstrate in this issue of the AJP. Using tissue microarray data in conjunction with breast tumor sections and extensive patient survival data, Sloan et al demonstrate that strong stromal Cav-1 expression is associated with smaller breast tumor size and grade, and is highly predictive of increased survival (Figure 1). Patients with positive expression of stromal Cav-1 had a 91% 10-year survival rate, vs. a 43% survival rate for patients lacking stromal Cav-1 expression. Importantly, there was no correlation between Cav-1 expression in the tumor epithelium and clinical outcome in either tissue arrays or tumor sections.10Sloan 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.The Am J Pathol. 2009; 174: 2035-2043Abstract Full Text Full Text PDF PubMed Scopus (172) Google ScholarWitkiewicz, Dasgupta, and colleagues11Witkiewicz AK Dasgupta A Sotgia F Mercier I Pestell RG Sabel M Kleer CG Brody JR Lisanti MP An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.Am J Pathol. 2009; 174: 2023-2034Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar independently investigated the clinical significance of stromal Cav-1 expression in a breast tumor tissue microarray. The presence of stromal Cav-1 was strongly associated with tumor size, local spread to lymph nodes, and progression-free survival in tamoxifen-treated and untreated patients. Again, tumor Cav-1 expression did not correlate with either of the described metrics.11Witkiewicz AK Dasgupta A Sotgia F Mercier I Pestell RG Sabel M Kleer CG Brody JR Lisanti MP An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.Am J Pathol. 2009; 174: 2023-2034Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar Strikingly, both studies found that stromal Cav-1 expression predicted patient survival independent of estrogen receptor, progesterone receptor, or HER2 status.10Sloan 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.The Am J Pathol. 2009; 174: 2035-2043Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 11Witkiewicz AK Dasgupta A Sotgia F Mercier I Pestell RG Sabel M Kleer CG Brody JR Lisanti MP An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.Am J Pathol. 2009; 174: 2023-2034Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar Results from these two clinical studies suggest that stromal Cav-1 expression may be a new independent prognostic factor for long-term survival and disease recurrence in breast cancer patients, and the tamoxifen data suggest that expression of stromal Cav-1 may also predict resistance to treatment.As with any exciting study, the intriguing data raise a number of questions that sow the soil for future studies. Principle among these questions is whether Cav-1 is a surrogate or a functional biomarker (summarized in Figure 2).Figure 2Three possible scenarios by which Cav-1 loss mediates tumor invasion in the breast tumor microenvironment. Left: Schematic view of a cross-sectioned normal mammary duct. An inner layer of luminal epithelial cells (red) is surrounded basally by myoepithelial cells (blue) and basement membrane (black). Right: Loss of Cav-1 could coincide with or result in 3 distinct scenarios. Scenario 1: Absence of Cav-1 coincides with loss of myoepithelial cells (MEPs). MEPs are more often found in benign breast lesions than in advanced carcinomas.21Gusterson BA Warburton MJ Mitchell D Ellison M Neville AM Rudland PS Distribution of myoepithelial cells and basement membrane proteins in the normal breast and in benign and malignant breast diseases.Cancer Res. 1982; 42: 4763-4770PubMed Google Scholar Since Cav-1 is expressed by MEPs, MEP loss would be reflected by an absence of Cav-1 staining. Scenario 2: Loss of Cav-1 mediates loss of MEP function, resulting in invasive ductal carcinoma. Cancer-associated MEPs behave distinctly from normal MEPs, which function as tumor suppressors.16Barsky SH Karlin NJ Myoepithelial cells: autocrine and paracrine suppressors of breast cancer progression.J Mammary Gland Biol Neoplasia. 2005; 10: 249-260Crossref PubMed Scopus (95) Google Scholar Loss of Cav-1 may directly alter the secretion profile of MEPs such that they are unable to regulate architecture, ultimately resulting in tumor invasion. Scenario 3: Loss of Cav-1 induces differentiation of surrounding fibroblasts to a carcinoma-associated fibroblast (CAF) phenotype. Normal breast fibroblasts express Cav-1.10Sloan 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.The Am J Pathol. 2009; 174: 2035-2043Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 11Witkiewicz AK Dasgupta A Sotgia F Mercier I Pestell RG Sabel M Kleer CG Brody JR Lisanti MP An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.Am J Pathol. 2009; 174: 2023-2034Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar Loss of Cav-1 in fibroblasts could directly initiate their transition to CAFs (green), which secrete a variety of factors to promote invasion and possibly inhibit the production of Cav-1 in other cell types (eg, MEPs), thereby further promoting invasion by the means described in Scenario 2.View Large Image Figure ViewerDownload Hi-res image Download (PPT)An argument for Cav-1 being a functional biomarker is that its lack of expression may reflect the physical absence of a Cav-1-expressing cell type (Figure 2, Scenario 1). While Cav-1 was not expressed in the normal mammary epithelium, both groups observed Cav-1 expression in myoepithelium, endothelium, and fibroblasts.10Sloan 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.The Am J Pathol. 2009; 174: 2035-2043Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 11Witkiewicz AK Dasgupta A Sotgia F Mercier I Pestell RG Sabel M Kleer CG Brody JR Lisanti MP An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.Am J Pathol. 2009; 174: 2023-2034Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar Whereas endothelial cells and fibroblasts have demonstrated roles in promoting tumor progression,7Bissell MJ Radisky D Putting tumours in context.Nat Rev Cancer. 2001; 1: 46-54Crossref PubMed Scopus (1710) Google Scholar myoepithelial cells (MEPs) function as natural tumor suppressors.16Barsky SH Karlin NJ Myoepithelial cells: autocrine and paracrine suppressors of breast cancer progression.J Mammary Gland Biol Neoplasia. 2005; 10: 249-260Crossref PubMed Scopus (95) Google Scholar, 17Adriance MC Inman JL Petersen OW Bissell MJ Myoepithelial cells: good fences make good neighbors.Breast Cancer Res. 2005; 7: 190-197Crossref PubMed Scopus (181) Google Scholar In a three-dimensional model of normal acini, it is the MEPs that confer polarity to luminal cells,18Gudjonsson T Ronnov-Jessen L Villadsen R Rank F Bissell MJ Petersen OW Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition.J Cell Sci. 2002; 115: 39-50Crossref PubMed Google Scholar and in a xenograft model of breast tumor progression, the presence of normal MEPs prevents conversion of the ductal carcinoma in situ phenotype to invasive ductal carcinoma.19Hu M Yao J Carroll DK Weremowicz S Chen H Carrasco D Richardson A Violette S Nikolskaya T Nikolsky Y Bauerlein EL Hahn WC Gelman RS Allred C Bissell MJ Schnitt S Polyak K Regulation of in situ to invasive breast carcinoma transition.Cancer Cell. 2008; 13: 394-406Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar This ‘guardian’ function of normal MEPs begins to be lost in situ and MEPs surrounding ductal carcinoma in situ are in fact quite abnormal.20Allinen M Beroukhim R Cai L Brennan C Lahti-Domenici J Huang H Porter D Hu M Chin L Richardson A Schnitt S Sellers WR Polyak K Molecular characterization of the tumor microenvironment in breast cancer.Cancer Cell. 2004; 6: 17-32Abstract Full Text Full Text PDF PubMed Scopus (1023) Google Scholar As tumors progress, MEPs are mysteriously reduced or absent (eg, in invasive breast tumors).21Gusterson BA Warburton MJ Mitchell D Ellison M Neville AM Rudland PS Distribution of myoepithelial cells and basement membrane proteins in the normal breast and in benign and malignant breast diseases.Cancer Res. 1982; 42: 4763-4770PubMed Google Scholar Whether MEPs have apoptosed, transdifferentiated, or migrated away is unknown, but it is quite possible that Cav-1 disappears with them. Indeed, enhanced tumor growth and invasion observed by Witkiewicz, Dasgupta et al to correlate with loss of Cav-1 expression are also noted consequences of MEP loss.22Man YG Tai L Barner R Vang R Saenger JS Shekitka KM Bratthauer GL Wheeler DT Liang CY Vinh TN Strauss BL Cell clusters overlying focally disrupted mammary myoepithelial cell layers and adjacent cells within the same duct display different immunohistochemical and genetic features: implications for tumor progression and invasion.Breast Cancer Res. 2003; 5: R231-R241Crossref PubMed Scopus (72) Google ScholarIf not a surrogate biomarker, Cav-1 may instead be a functional biomarker directly responsible for the tumor suppressor functions of MEPs (Figure 2, Scenario 2). Carcinoma-associated MEPs lose the ability to deposit an integral component of the laminin-rich basement membrane that surrounds breast epithelium, potentially robbing epithelial cells of signals crucial to maintaining their architecture,18Gudjonsson T Ronnov-Jessen L Villadsen R Rank F Bissell MJ Petersen OW Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition.J Cell Sci. 2002; 115: 39-50Crossref PubMed Google Scholar and secrete chemokines that may foster tumor growth and invasion.20Allinen M Beroukhim R Cai L Brennan C Lahti-Domenici J Huang H Porter D Hu M Chin L Richardson A Schnitt S Sellers WR Polyak K Molecular characterization of the tumor microenvironment in breast cancer.Cancer Cell. 2004; 6: 17-32Abstract Full Text Full Text PDF PubMed Scopus (1023) Google Scholar Loss of Cav-1 expression from MEPs, perhaps induced by factors secreted by either transformed epithelial cells or disrupted stroma, may skew their secretory profile and ultimately promote an invasive phenotype.Witkiewicz et al11Witkiewicz AK Dasgupta A Sotgia F Mercier I Pestell RG Sabel M Kleer CG Brody JR Lisanti MP An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers.Am J Pathol. 2009; 174: 2023-2034Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar make a case for Cav-1 loss exerting its effects in the fibroblast component of the microenvironment (Figure 2, Scenario 3). This group has recently shown that loss of Cav-1 induces a carcinoma-associated fibroblast (CAF) phenotype,23Sotgia F Del Galdo F Casimiro MC Bonuccelli G Mercier I Whitaker-Menezes D Daumer KM Zhou J Wang C Katiyar S Xu H Bosco E Quong AA Aronow B Witkiewicz AK Minetti C Frank PG Jimenez SA Knudsen ES Pestell RG Lisanti MP Caveolin-1−/− null mammary stromal fibroblasts share characteristics with human breast cancer-associated fibroblasts.Am J Pathol. 2009; 174: 746-761Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar which actively participates in tumor progression.24Olumi AF Grossfeld GD Hayward SW Carroll PR Tlsty TD Cunha GR Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium.Cancer Res. 1999; 59: 5002-5011PubMed Google Scholar, 25Orimo A Gupta PB Sgroi DC Arenzana-Seisdedos F Delaunay T Naeem R Carey VJ Richardson AL Weinberg RA Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion.Cell. 2005; 121: 335-348Abstract Full Text Full Text PDF PubMed Scopus (2839) Google Scholar Loss of Cav-1 expression may directly mediate transition to the CAF phenotype and promote tumor growth by either attenuating the activity of a tumor suppressor (eg, retinoblastoma tumor suppressor23Sotgia F Del Galdo F Casimiro MC Bonuccelli G Mercier I Whitaker-Menezes D Daumer KM Zhou J Wang C Katiyar S Xu H Bosco E Quong AA Aronow B Witkiewicz AK Minetti C Frank PG Jimenez SA Knudsen ES Pestell RG Lisanti MP Caveolin-1−/− null mammary stromal fibroblasts share characteristics with human breast cancer-associated fibroblasts.Am J Pathol. 2009; 174: 746-761Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar), activating transforming growth factor-β expression, and/or modulating transforming growth factor-β receptor activity.26Bhowmick NA Chytil A Plieth D Gorska AE Dumont N Shappell S Washington MK Neilson EG Moses HL TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia.Science. 2004; 303: 848-851Crossref PubMed Scopus (1121) Google Scholar, 27Radisky DC Bissell MJ Cancer. Respect thy neighbor!.Science. 2004; 303: 775-777Crossref PubMed Scopus (94) Google ScholarRegardless of which scenario may be operating, it is of interest that neither study positively correlated stromal Cav-1 expression with distant metastases (ie, M-stage). Further, while the offspring of Cav-1 null mice and Her-2/neu mice (which develop mammary-specific tumors) established by Sloan et al10Sloan 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.The Am J Pathol. 2009; 174: 2035-2043Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar developed tumors faster and required more rapid sacrificing than Her-2/neu counterparts, they did not show increased lung metastases. In light of the survival data, however, the simple question remains: why do patients lacking stromal Cav-1 expression die so fast? It is well accepted that metastatic growths are the cause of breast cancer-related deaths, so determining whether lack of stromal Cav-1 expression at the primary site is related to escape from tumor dormancy at the secondary site in already established mouse models14Williams TM Sotgia F Lee H Hassan G Di Vizio D Bonuccelli G Capozza F Mercier I Rui H Pestell RG Lisanti MP Stromal and epithelial caveolin-1 both confer a protective effect against mammary hyperplasia and tumorigenesis: caveolin-1 antagonizes cyclin D1 function in mammary epithelial cells.Am J Pathol. 2006; 169: 1784-1801Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar may yield intriguing results. Elaborating on such studies by deleting Cav-1 in specific cell types (eg, MEPs, adipocytes) could reveal whether Cav-1 expression is crucial only within certain cell populations and also pinpoint which cell type(s) to use for interrogation of the molecular mechanisms by which reduced Cav-1 expression enhances tumor growth and invasion.Given the striking prognostic finding of Cav-1 loss in the tumor microenvironment, a final point of discussion is whether stromal Cav-1 also provides a meaningful therapeutic target. Forced expression of Cav-1 in transformed mammary epithelial cells significantly inhibits their growth14Williams TM Sotgia F Lee H Hassan G Di Vizio D Bonuccelli G Capozza F Mercier I Rui H Pestell RG Lisanti MP Stromal and epithelial caveolin-1 both confer a protective effect against mammary hyperplasia and tumorigenesis: caveolin-1 antagonizes cyclin D1 function in mammary epithelial cells.Am J Pathol. 2006; 169: 1784-1801Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar; thus, exploring the biological functions and molecular regulation of Cav-1 in developing mammary stroma as well as in normal adult mammary stroma may further motivate the development of strategies to enhance tissue specific Cav-1 expression in breast cancer patients. For now, the two studies presented in this issue of the AJP provide additional validation that the microenvironment is an important and potentially powerful source of clinical information to predict patient outcome, and demonstrate specifically that stromal Cav-1 may be a valuable clinical marker. Determining whether stromal Cav-1 functions to directly suppress tumor growth, and uncovering the factors which regulate its expression, may also reveal novel therapeutic avenues and help unveil who is watching the vigilant watchman. Need it be said again that no cell is an island, and in tissue-specificity and cancer, context is supreme. Decades ago, seminal recombination experiments illustrated the dominant role of mammary mesenchyme in directing epithelial development1Cunha GR Young P Christov K Guzman R Nandi S Talamantes F Thordarson G Mammary phenotypic expression induced in epidermal cells by embryonic mammary mesenchyme.Acta Anat (Basel). 1995; 152: 195-204Crossref PubMed Scopus (71) Google Scholar, 2Propper A Gomot L Control of chick epidermis differentiation by rabbit mammary mesenchyme.Experientia. 1973; 29: 1543-1544Crossref PubMed Scopus (25) Google Scholar, 3Sakakura T Nishizuka Y Dawe CJ Mesenchyme-dependent morphogenesis and epithelium-specific cytodifferentiation in mouse mammary gland.Science. 1976; 194: 1439-1441Crossref PubMed Scopus (254) Google Scholar and strongly suggested that the microenvironment also plays a significant role in the manifestation of carcinoma. More direct evidence for such functions came from a study demonstrating that an unadulterated microenvironment can suppress the malignant phenotype and re-direct tumor cells to give rise to normally functioning tissues and, indeed, healthy mice.4Mintz B Illmensee K Normal genetically mosaic mice produced from malignant teratocarcinoma cells.Proc Natl Acad Sci USA. 1975; 72: 3585-3589Crossref PubMed Scopus (897) Google Scholar One may wonder why such a stunning finding did not convince the scientific community to pay more attention to the role of context. The answers are complex; however, concomitantly with this finding, the roles of oncogenes and mutations were being discovered. That excitement carried the day, especially because no one subsequently determined whether or not these mice generated from malignant cells contained tumorigenic mutations, and no new group reproduced the work. The following decade saw the discovery that even potent oncogenes could be ruled by context,5Dolberg DS Bissell MJ Inability of Rous sarcoma virus to cause sarcomas in the avian embryo.Nature. 1984; 309: 552-556Crossref PubMed Scopus (147) Google Scholar and recently it was shown that similar reprogramming of metastatic melanoma by an embryonic microenvironment was possible.6Kulesa PM Kasemeier-Kulesa JC Teddy JM Margaryan NV Seftor EA Seftor RE Hendrix MJ Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment.Proc Natl Acad Sci USA. 2006; 103: 3752-3757Crossref PubMed Scopus (189) Google Scholar There are many more examples that are not as clear cut, but are nevertheless compelling. The extensive literature of two-stage carcinogenesis, namely initiation and progression, indeed clearly indicates that “initiation” and DNA damage alone are not sufficient to allow carcinogenesis. These findings imply that ‘once a tumor or an oncogene, not always a tumor or an oncogene.’ A renewed focus on the tumor microenvironment as a therapeutic target7Bissell MJ Radisky D Putting tumours in context.Nat Rev Cancer. 2001; 1: 46-54Crossref PubMed Scopus (1710) Google Scholar has also led to the recognition that markers within the microenvironment could have predictive power. Two recently published reports identifying ‘stromal signatures’ in breast cancer patients prognostic for patient survival8Finak G Bertos N Pepin F Sadekova S Souleimanova M Zhao H Chen H Omeroglu G Meterissian S Omeroglu A Hallett M Park M Stromal gene expression predicts clinical outcome in breast cancer.Nat Med. 2008; 14: 518-527Crossref PubMed Scopus (1264) Google Scholar and predictive of response to chemotherapeutic treatment9Farmer P Bonnefoi H Anderle P Cameron D Wirapati P Becette V Andre S Piccart M Campone M Brain E Macgrogan G Petit T Jassem J Bibeau F Blot E Bogaerts J Aguet M Bergh J Iggo R Delorenzi M A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer.Nat Med. 2009; 15: 68-74Crossref PubMed Scopus (479) Google Scholar provide proof of this concept. In the current issue of The American Journal of Pathology, two independent studies10Sloan 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 outc" @default.
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• W76295024 cites W1968807484 @default.
• W76295024 cites W1982903815 @default.
• W76295024 cites W1998016535 @default.
• W76295024 cites W1999743098 @default.
• W76295024 cites W2004544448 @default.
• W76295024 cites W2006171435 @default.
• W76295024 cites W2007470455 @default.
• W76295024 cites W2010069724 @default.
• W76295024 cites W2015847779 @default.
• W76295024 cites W2023284036 @default.
• W76295024 cites W2023906705 @default.
• W76295024 cites W2024585566 @default.
• W76295024 cites W2031300004 @default.
• W76295024 cites W2036356664 @default.
• W76295024 cites W2042616537 @default.
• W76295024 cites W2043757927 @default.
• W76295024 cites W2049820772 @default.
• W76295024 cites W2062565240 @default.
• W76295024 cites W2099915274 @default.
• W76295024 cites W2101037339 @default.
• W76295024 cites W2133851039 @default.
• W76295024 cites W2154453972 @default.
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