Breast cancer milieu -- Progression, tamoxifen sensitivity, and DNA reversion

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.

PROGRESSION OF BREAST CANCER

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.

LOCAL CELLS AFFECT TAMOXIFEN SENSITIVITY

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.