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PTEN in the Breast Tumor Microenvironment
Tumor Cell Biology II
Carcinoma progression is accepted as a multi-stage process requiring progressive genetic alterations within the epithelial cells that act in a cell autonomous fashion to drive tumor progression. At the same time, the many other cell types in the tumor microenvironment, including stromal fibroblasts, endothelial cells, and various immune cells like macrophages, are increasingly appreciated as components of a complex biological network akin to an organ system that affect tumor progression and metastasis in a cell non-autonomous fashion. A major question raised by the model of microenvironment as active partner in tumor progression is the identity of the genes that act from within the microenvironment to affect tumor progression. Through collaborative efforts utilizing genetic approaches both in human and mouse systems, the PTEN tumor suppressor has been identified as a gene that acts from tumor stromal fibroblasts within the breast tumor microenvironment. This work leads to the hypothesis that mutation in the PTEN tumor suppressor in breast tumor stromal fibroblasts causes changes in the composition and activity of the extracellular matrix, and that these changes accelerate breast tumor progression and metastasis through both effects directly on tumor cells and effects on other tumor microenvironment cell types. We will test this hypothesis using a combination of molecular genetic and genetic approaches. As a first step, these studies will focus on defining mechanisms by which a mutation of mouse Pten gene in breast tumor fibroblasts alters gene expression and intracellular signaling in tumor stromal fibroblasts. Our ultimate goal is to determine if the key changes identified in mouse models translate to human patient samples, and to correlate these to clinical parameters.
Tumor suppressor genes are similar to the brakes on a car, providing one control that prevents cells from moving in the wrong direction and towards cancer. In early stages of the disease these genes get broken (or mutated), and cells begin to move out of control towards cancer. The PTEN tumor suppressor is a major human tumor suppressor gene involved in breast cancer. As for all tumor suppressor genes, research has focused mainly on the action of these genes within the tumor cells themselves. However, it is becoming clear that these genes can also become broken/mutated in non-tumor cells that surround the growing tumor. These non-tumor cells are called collectively the tumor microenvironment. The tumor microenvironment is like a neighborhood around the tumor cells, and just as a neighborhood can affect the behavior of children, these cells can have a good effect or a bad effect on how the tumor develops. Thus, mutation of PTEN in the tumor microenvironment could influence the nascent tumor cells in a bad way. We have used mouse models to demonstrate just this fact, that mutation of PTEN in one type of cells in the tumor microenvironment, termed stromal fibroblasts, can rapidly increase the growth of breast tumors. Through these experiments, we have created a mouse model that more accurately reflects human breast cancer, with mutation in the Her2/neu gene in the breast tumor cells (occurring in 30% of cancer patients) and mutation in PTEN in the stromal fibroblasts (occurring in about 15-20% of human breast cancer patients). In the proposed work, mouse models and molecular approaches will be used to understand how this specific genetic change in the non-cancer stromal cells affects growth and spread of the tumor cells. This work will be directly relevant to human breast cancer, as it will lead to better ways to diagnose and treat this disease in specific patients with PTEN mutations in the tumor microenvironment.