Caveolin-1−/− Null Mammary Stromal Fibroblasts Share Characteristics with Human Breast Cancer-Associated Fibroblasts

Sotgia, Federica; Galdo, Francesco Del; Casimiro, Mathew C.; Bonuccelli, Gloria; Mercier, Isabelle Le; Whitaker‐Menezes, Diana; Daumer, Kristin M.; Zhou, Jie; Wang, Chenguang; Katiyar, Sanjay; Xu, Huan; Bosco, Emily E.; Quong, Andrew A.; Aronow, Bruce J.; Witkiewicz, Agnieszka K.; Minetti, Carlo; Frank, Philippe G.; Jimenez, Sergio A.; Knudsen, Erik S.; Pestell, Richard G.; Lisanti, Michael P.

doi:10.2353/ajpath.2009.080658

Cited by 111 publications

(128 citation statements)

References 42 publications

(46 reference statements)

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“…Consistent with this, recent studies suggest that a loss of caveolin-1 expression may be a marker of the cancer-associated fibroblast phenotype, further linking depletion of caveolin-1 with a pathological fibroblast phenotype. 37,38 We have previously demonstrated that membrane-associated PTEN levels and activity are low in IPF fibroblasts. 1 This results in pathological activation of the PI3K/ Akt signal pathway and confers IPF fibroblasts with the ability to elude the antiproliferative properties of polymerized type I collagen.…”

Section: Discussionmentioning

confidence: 99%

Pathologic Caveolin-1 Regulation of PTEN in Idiopathic Pulmonary Fibrosis

Xia

Khalil

Kahm

et al. 2010

The American Journal of Pathology

134

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Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder refractory to current pharmacological therapies. Fibroblasts isolated from IPF patients display pathological activation of PI3K/Akt caused by low PTEN phosphatase activity. This enables these cells to escape the negative proliferative properties of polymerized collagen. The mechanism underlying low PTEN activity in IPF fibroblasts is unclear, but our prior studies indicate that membrane-associated PTEN expression is decreased in these cells. Caveolin-1 is an integral membrane protein whose expression is decreased in IPF lung tissue, but how low caveolin-1 contributes to pathological fibrosis is incompletely understood. The objective of this study was to examine the hypothesis that caveolin-1 regulates PTEN function in IPF fibroblasts. Here we demonstrate that caveolin-1 expression is a determinant of membrane PTEN levels and show that PTEN interacts with caveolin-1 via its caveolin-1-binding sequence. We demonstrate that caveolin-1 expression is low in IPF fibroblasts and that this correlates with low membrane PTEN levels , whereas overexpression of caveolin-1 restores membrane PTEN levels, inhibits Akt phosphorylation, and suppresses proliferation. We demonstrate that caveolin-1 and PTEN expression are low in myofibroblasts within IPF fibroblastic foci. These data indicate that IPF fibroblasts display low caveolin-1 expression, which results in low membrane-associated PTEN expression. This creates a membrane microenvironment depleted of inhibitory phosphatase activity, facilitating the aberrant activation PI3K/Akt and pathological proliferation. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

Pathologic Caveolin-1 Regulation of PTEN in Idiopathic Pulmonary Fibrosis

Xia

Khalil

Kahm

et al. 2010

The American Journal of Pathology

134

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“…We have previously demonstrated that Cav-1 (-/-) mammary stromal fibroblasts behave like cancerassociated fibroblasts 13 and secrete or express elevated levels of a number of pro-inflammatory growth factors/cytokines (such as PDGF, VEGF, HGF, MIP2, MIP1-alpha, GM-CSF, TARC, L-Selectin and IL-6/11/10/13) 13 involved in regulating lymphocyte, neutrophil and macrophage recruitment. Thus, an absence of stromal Cav-1 in mammary fibroblasts may exacerbate local inflammation, thereby promoting an EMT-like genetic program in neighboring epithelial cells via paracrine secreted factors, leading to DCIS recurrence and progression to invasive breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the Cav-1 (-/-) mammary stromal micro-enviroment may foster the development or propagation of epithelial cancer stem cells, leading to DCIS-like lesion formation, and local microinvasion. 15 In this regard, Cav-1 (-/-) mammary stromal fibroblasts also overexpress a subset of ES-cell related genes, suggesting that they may resemble mesenchymal stem cells; 13 similarly, human breast cancer-associated fibroblasts that lack Cav-1 protein expression, also show the overexpression of stem/progenitor cell-associated genes. 9,14 Overall, this is consistent with a model in which the mammary stromal micro-enviroment controls the "stemness" of the epithelial compartment, leading towards tumorigenesis and invasiveness.…”

Section: Methodsmentioning

confidence: 99%

Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer

Witkiewicz

Dasgupta

Nguyen

et al. 2009

Cancer Biology & Therapy

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Here, we determined the possible association of stromal caveolin-1 (Cav-1) levels with DCIS recurrence and/or progression to invasive breast cancer. An initial cohort of 78 DCIS patients with follow-up data was examined. As ER-positivity was associated with recurrence, we focused our analysis on this subset of 56 patients. In this group, we observed that DCIS progressed to invasive breast cancer in ~14% of the patient population (8/56), in accordance with an expected progression rate of 12-15%. Nearly ninety percent of DCIS patients (7/8) that underwent recurrence to invasive breast cancer had reduced or absent levels of stromal Cav-1. Remarkably, an absence of stromal Cav-1 (score = 0) was specifically associated with early disease progression to invasive breast cancer, with reduced time to recurrence and higher recurrence rate. All DCIS patients with an absence of stromal Cav-1 underwent some form of recurrence (5/5) and the majority (4/5) underwent progression to invasive breast cancer. This represents an overall cumulative incidence rate of 100% for recurrence and 80% for progression. An absence of stromal Cav-1 in DCIS lesions was also specifically associated with the presence of inflammatory cells. Conversely, ninety-seven percent of ER(+) DCIS patients (35/36) with high levels of stromal Cav-1 (score = 2) did not show any invasive recurrence over the duration of follow-up (4-208 mo), and 89% of such patients are estimated to remain free of invasive recurrence, even after 15 y. Thus, determination of stromal Cav-1 levels may be a useful new biomarker for guiding the treatment of ER(+) DCIS patients.

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“…23,24 Thus, we next evaluated if ethanol exposure induces myofibroblast differentiation by immunoblot analysis, with antibodies directed against the myofibroblast markers vimentin and SMA. Figure 1C shows that fibroblasts treated with ethanol display the upregulation of SMA and vimentin, relative to untreated cells.…”

Section: Resultsmentioning

confidence: 99%