Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 down-regulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy

Mercier, Isabelle Le; Casimiro, Mathew C.; Wang, Chenguang; Rosenberg, Anne; Quong, Judy N.; Minkeu, Alimatou; Allen, Kathleen G.; Danilo, Christiane; Sotgia, Federica; Bonuccelli, Gloria; Jasmin, Jean-François; Xu, Huan; Bosco, Emily E.; Aronow, Bruce A.; Witkiewicz, Agnieszka K.; Pestell, Richard G.; Knudsen, Erik S.; Lisanti, Michael P.

doi:10.4161/cbt.7.8.6220

Cited by 139 publications

(144 citation statements)

References 36 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…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: Methodssupporting

confidence: 85%

“…Consistent with this hypothesis, human breast cancer-associated fibroblasts show a loss of Cav-1 protein expression, as compared with matched normal human fibroblasts obtained from the same patients, in eight out of 11 breast cancer patients examined. 14 Interestingly, Cav-1 (-/-) mice develop high-grade DCIS-like lesions, with micro-invasion (as evidenced by a discontinuous myo-epithelial cell layer), and extensive mammary stromal angiogenesis, when challenged with estrogen. 15 As Cav-1 is not normally expressed in luminal mammary epithelial cells, while mammary stromal fibroblasts abundantly express Cav-1, this DCIS-like phenotype observed in estrogen-stimulated Cav-1 (-/-) null mice may be a "stromal phenomenon".…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Witkiewicz

Dasgupta

Nguyen

et al. 2009

Cancer Biology & Therapy

Self Cite

119

150

View full text Add to dashboard Cite

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.

show abstract

Section: Methodssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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

Witkiewicz

Dasgupta

Nguyen

et al. 2009

Cancer Biology & Therapy

Self Cite

119

150

View full text Add to dashboard Cite

show abstract

“…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

133

View full text Add to dashboard Cite

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

show abstract

“…Previous studies have shown that a loss of Cav-1 expression is a hallmark of the aggressive CAF phenotype. 13 Mammary fibroblasts derived from Cav-1 null (-/-) mice display several CAF-like features, with enhanced contraction-retraction and increased secretion of HGF, PDGF, VEGF and collagen-I. 14 Finally, transient siRNA-mediated knock-down of Cav-1 in fibroblasts is sufficient to promote a CAF-like phenotype, with activated TGFbeta signaling.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution

et al. 2010

Self Cite

View full text Add to dashboard Cite

Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a "lethal tumor microenvironment." Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a "metabolic" and "mutagenic" motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, we show that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress and aerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria are removed from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress. As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulate mitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the "Reverse Warburg effect"). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to induce genomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressive behavior. Finally, we directly demonstrate that nitric oxide (No) over-production, secondary to Cav-1 loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of this notion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or No inhibitors (L-NAMe) was sufficient to reverse many of the cancer-associated fibroblast phenotypes that we describe. thus, cancer cells use "oxidative stress" in adjacent fibroblasts (1) as an "engine" to fuel their own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability. We also present evidence that the "field effect" in cancer biology could also be related to the stromal production of RoS and No species. eNoS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunction in adjacent fibroblasts that do not express eNoS. As such, the effects of stromal oxidative stress can be laterally propagated, amplified and are effectively "contagious"-spread from cell-to-cell like a virus-creating an "oncogenic/mutagenic" field promoting widespread DNA damage. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolutionA new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells ROS are eliminated by anti-oxidant enzymes, such as superoxide dismutases, the peroxiredoxins and glutathione peroxidases. High ROS levels may result in significant cellular damage and induce oxidative stress, which i...

show abstract

Human breast cancer-associated fibroblasts (CAFs) show caveolin-1 down-regulation and RB tumor suppressor functional inactivation: Implications for the response to hormonal therapy

Cited by 139 publications

References 36 publications

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

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

Pathologic Caveolin-1 Regulation of PTEN in Idiopathic Pulmonary Fibrosis

Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution

Contact Info

Product

Resources

About