%0 Journal Article %J Neoplasia %D 2013 %T Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics %A Dumont, Nancy %A Liu, Bob %A DeFilippis, Rosa Anna %A Hang Chang %A Rabban, Joseph T %A Karnezis, Anthony N %A Tjoe, Judy A %A Marx, James %A Parvin, Bahram %A Tlsty, Thea D %K Animals %K Breast %K Cell Line, Tumor %K Cell Transformation, Neoplastic %K Coculture Techniques %K Epithelial Cells %K Extracellular Matrix %K Extracellular Signal-Regulated MAP Kinases %K Female %K Fibroblasts %K Humans %K Lung Neoplasms %K Mammary Neoplasms, Experimental %K Neoplasm Metastasis %K Phenotype %K Proto-Oncogene Proteins c-jun %K rho GTP-Binding Proteins %K Signal Transduction %K Transforming Growth Factor beta %X

A wealth of evidence has now demonstrated that the microenvironment in which a tumorigenic cell evolves is as critical to its evolution as the genetic mutations it accrues. However, there is still relatively little known about how signals from the microenvironment contribute to the early events in the progression to malignancy. To address this question, we used a premalignant mammary model to examine how fibroblasts, and the extracellular matrix (ECM) proteins they secrete, influence progression to malignancy. Their effect on metastatic malignant cells was also assessed for comparison. We found that carcinoma-associated fibroblasts, and the distinct aligned ECM they deposit, can cause both premalignant and malignant mammary epithelial cells to assume a mesenchymal morphology that is associated with increased dissemination and metastasis, while benign reduction mammoplasty fibroblasts favor the maintenance of an epithelial morphology and constrain early dissemination, tumor growth, and metastasis. Our results suggest that normalizing the organization of the ECM could be effective in limiting systemic dissemination and tumor growth.

%B Neoplasia %V 15 %P 249-62 %8 2013 Mar %G eng %N 3 %0 Journal Article %J Cancer Discov %D 2012 %T CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues %A DeFilippis, Rosa Anna %A Hang Chang %A Dumont, Nancy %A Rabban, Joseph T %A Chen, Yunn-Yi %A Fontenay, Gerald V %A Berman, Hal K %A Gauthier, Mona L %A Zhao, Jianxin %A Hu, Donglei %A Marx, James J %A Tjoe, Judy A %A Ziv, Elad %A Febbraio, Maria %A Kerlikowske, Karla %A Parvin, Bahram %A Tlsty, Thea D %K Adipocytes %K Animals %K Antigens, CD36 %K Breast Neoplasms %K Cell Differentiation %K Female %K Humans %K Mammography %K Mice %K Mice, Knockout %K Risk Factors %K Signal Transduction %K Stromal Cells %X

UNLABELLED: Although high mammographic density is considered one of the strongest risk factors for invasive breast cancer, the genes involved in modulating this clinical feature are unknown. Tissues of high mammographic density share key histologic features with stromal components within malignant lesions of tumor tissues, specifically low adipocyte and high extracellular matrix (ECM) content. We show that CD36, a transmembrane receptor that coordinately modulates multiple protumorigenic phenotypes, including adipocyte differentiation, angiogenesis, cell-ECM interactions, and immune signaling, is greatly repressed in multiple cell types of disease-free stroma associated with high mammographic density and tumor stroma. Using both in vitro and in vivo assays, we show that CD36 repression is necessary and sufficient to recapitulate the above-mentioned phenotypes observed in high mammographic density and tumor tissues. Consistent with a functional role for this coordinated program in tumorigenesis, we observe that clinical outcomes are strongly associated with CD36 expression.

SIGNIFICANCE: CD36 simultaneously controls adipocyte content and matrix accumulation and is coordinately repressed in multiple cell types within tumor and high mammographic density stroma, suggesting that activation of this stromal program is an early event in tumorigenesis. Levels of CD36 and extent of mammographic density are both modifiable factors that provide potential for intervention.

%B Cancer Discov %V 2 %P 826-39 %8 2012 Sep %G eng %N 9 %R 10.1158/2159-8290.CD-12-0107