In Vivo Analysis of Alternative Modes of Breast Cancer Cell Invasion

摘要

The purpose of this funded program was to examine the regulation of cell shape and movement used by mammary tumor cells during local invasion and metastasis. We found that collagen-I, found in aggressive primary human breast tumors, promotes an invasive phenotype in a 3D culture system, through an increase in Rho/ROCK-mediated actomyosin contractility in HER2/neu-expressing mouse mammary tumor cells. High contractility is normally associated with the more aggressive basallike breast cancers, providing evidence that collagen-I may be promoting a more aggressive phenotype in primary breast tumors. In addition, we have evidence that invasive properties of mammary tumors depends on the extracellular matrix environment, rather than expression of invasion- associated (mesenchymal) genes alone. Importantly, we have developed a novel 3D model of local invasion that occurs at the stromal interface of solid mammary tumors. This model was used to identify c-Src and ILK as critical mediators of EMT and local invasion, using small-molecule inhibitors. More importantly, we showed that changes in cell shape and 3D arrangement dramatically altered the sensitivity to ionizing radiation-induced death. This results have important clinical implications for the treatment of both primary and secondary tumors in metastatic breast cancer.