Loss of Suppressors in Surrounding Tissues Spur Breast Tumor Growth

Mutations that block the activity of the Pten tumor suppressor gene cause mammary stromal fibroblasts to secrete a potent cocktail of signaling molecules that can cause other cell types to undergo transformation into cancer cells.

The molecular soup released by mutated fibroblasts is referred to as the secretome. Investigators at Ohio State University (Columbus, USA) examined how the secretome affects the behavior of neighboring epithelial cells, and reported their findings in the December 18, 2011, online edition of the journal Nature Cell Biology that the most critical effect was inhibition of Pten.

Pten is one of the most commonly lost tumor suppressors in human cancer. During tumor development, mutations and deletions of Pten occur that inactivate its enzymatic activity leading to increased cell proliferation and reduced cell death. Frequent genetic inactivation of Pten occurs in glioblastoma, endometrial cancer, prostate cancer, and reduced expression is found in many other tumor types such as lung and breast cancer. When the PTEN enzyme is functioning properly, it acts as part of a chemical pathway that signals cells to stop dividing and causes cells to undergo programmed cell death (apoptosis) when necessary. These functions prevent uncontrolled cell growth that can lead to the formation of tumors. There is also evidence that the protein made by the PTEN gene may play a role in both cell movement and adhesion of cells to surrounding tissues.

Results of the current study showed that loss of Pten resulted in the downregulation of the microRNA miR-320 and the upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2). ETS transcriptions factors, such as ETS2, regulate numerous genes and are involved in stem cell development, cell senescence and death, and tumorigenesis. The abundance of ETS2 activated a number of genes that caused the fibroblasts to secrete more than 50 factors that stimulated the proliferation and invasiveness of nearby cancer cells.

“Our study is the first to define a specific pathway in tumor fibroblasts that reprograms gene activity and the behavior of multiple cell types in the tumor microenvironment, including tumor cells themselves,” said senior author Dr. Michael Ostrowski, professor of molecular and cellular biochemistry at Ohio State University. “Along with increasing basic knowledge about how tumors grow and spread, these findings have direct translational implications for the treatment of breast-cancer patients.”

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