Influence of the cellular microenvironment on breast cancer

This month The American Journal of Pathology highlights the influence of the cellular microenvironment on breast cancer by promoting three articles from the current issue.

These articles describe advances in our understanding of progression of breast cancer, local cells affecting tamoxifen sensitivity, and epigenetic reversion of breast cancer DNA. The three papers appear in the May issue of the AJP, with breast cancer DNA reversion highlighted on the cover.

Researchers have identified loss of Fiblin-2 as a marker of breast cancer progression since the protein is expressed by normal breast cells but lost in breast cancer cell lines and invasive breast tumors. As further confirmation of Fibulin-2's anti-invasion effect, reintroduction of the protein into Fibulin-2-negative breast cancer cells resulted in decreased cell migration and invasion in vitro.

Fibulin-2 is a known component of the extracellular matrix (the supportive protein structure surrounding cells) and is thought to be critical for cell migration during wound healing. However, loss of Fibulin-2 in breast cancer may lead to changes in the environment surrounding, and confining, cancer cells, thus enabling cancer cells to migrate from their original site to other locations.

Fibulin-2's potential involvement in breast cancer spread may provide prognostic implications if loss of its expression can be directly correlated with the transition from noninvasive breast cancer to recurrent and/or invasive breast cancer. Future studies will explore the exact mechanisms by which Fibulin-2 mediates its anti-invasion effect.

This work was lead by Dr. Michael A. Hollingsworth at the University of Nebraska Medical Center, Omaha, Nebraska, and supported by the Department of Defense and the National Institutes of Health.

Yi CH, Smith DJ, West WW, Hollingsworth MA. Loss of Fibulin-2 expression is associated with breast cancer progression. Am J Pathol 2007 170: 1535,1545.

Breast cancer cells that express estrogen receptor (ER) can be treated with tamoxifen only as long as they remain sensitive to the drug. Resistance to tamoxifen is a common problem in breast cancer treatment, but researchers are identifying the factors that influence sensitivity versus resistance.

When tamoxifen-sensitive, premalignant breast cancer cells were cultured with fibroblasts derived from ER-negative tumors, breast cancer cells became less sensitive to tamoxifen. Further, these cells were also less sensitive to inhibitors of cell growth. Conversely, tamoxifen resistance could not be restored in tamoxifen-resistant, malignant breast cancer cells by incubating with fibroblasts from ER-positive tumors.

These data demonstrate that fibroblasts influence the sensitivity of breast cancer cells to tamoxifen. Fibroblasts represent major components of the extracellular environment and perform important roles in maintaining that environment and influencing cell growth. Future research is directed at identifying the growth factors and other proteins released from fibroblasts involved in modulating these effects on breast cancer cells.

Studies were directed by Dr. Malathy P.V. Shekhar from Karmanos Cancer Institute and Wayne State University School of Medicine, Detroit, Michigan and funded by the US Army Medical Research and Materiel Command.

Shekhar MPV, Santner S, Carolin KA, Tait L. Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am J Pathol 2007 170:1546,1560.

Using breast cancer cells, researchers have demonstrated that cancer phenotype can be reversibly altered by manipulations other than genetic means. Breast cancer cells grown in 3-D culture can be induced to form normal breast duct-like structures, as opposed to dense cell masses, by activating or inhibiting specific signaling pathways, including antibody binding to the extracellular matrix protein fibronectin.

In addition, cancer cell DNA, which has been shown previously to resist enzymatic digestion, could be rendered accessible to enzyme digestion following reversion of its 3-D growth phenotype. Importantly, such reversion of breast cancer cells could be overturned by removing the reversion stimuli, resulting in a return to cancerous growth and resistance to enzymatic DNA digestion.

These data underscore the plasticity displayed by cancer cells: even after a cell adopts a cancerous phenotype, it can be manipulated to regain ,normal, 3-D structure, growth, and DNA organization (ie, enzyme accessibility). The intimate link between cellular growth phenotype and susceptibility to enzymatic DNA digestion suggests that analysis of DNA accessibility may have future diagnostic implications.

Research was overseen by Dr. Andrew J. Maniotis at the University of Illinois at Chicago, Chicago, Illinois, and supported by the Department of Energy, the National Institutes of Health, and the Norwegian Cancer Society.

Sandal T, Valyi-Nagy K, Spencer VA, Folberg R, Bissell MJ, Maniotis AJ. Epigenetic reversion of breast carcinoma phenotype is accompanied by changes in DNA sequestration as measured by AluI restriction enzyme. Am J Pathol 2007 170:1739,1749.

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