In Vivo Analysis of Alternative Modes of Breast Cancer Cell Invasion
Annual summary rept. 15 Apr 2007-14 Apr 2010
LONDON UNIV (UNITED KINGDOM) INST OF CANCER RESEARCH
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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 RhoROCK-mediated actomyosin contractility in HER2neu-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.
- Medicine and Medical Research