Abstract
Cell behavior and tissue homeostasis are not exclusively controlled by soluble chemical signals. Microenvironmental factors such as the extracellular matrix (ECM) arrangement, tissue architecture and mechanical forces are sources of signals capable of determining a cell's fate. Hippo-YAP (Hippo is a cascade of kinases that inactivate YAP, which is a transcription co-activator) regulates organ growth and size, and acts in mesenchymal stem cells as a sensor for mechanical signals from the microenvironment. Bioinformatics analysis of transcriptomes indicate the YAP-regulated genes are differentially expressed during mammary gland development and breast cancer progression. Preliminary results suggest that laminin-111 (LN1), an ECM protein that induces functional differentiation in the mammary epithelia, reduces nuclear YAP in non-malignant cells. Therefore, my hypothesis is that Hippo-YAP could be involved in the controlled tissue growth and quiescence of mammary gland, that LN1 and microenvironment viscosity influence Hippo-YAP and that these processes could be defective in breast cancer. I will use physiologically relevant assays of 3D culture that mimics branching morphogenesis of mammary epithelia and breast cancer progression in combination with molecular biology, biochemistry, bioinformatics and microscopy approaches. My prediction is that the conclusion of this project will bring details of the regulation of cell proliferation and invasion which are hallmarks of cancer progression, and that this information may be used to improve diagnosis, prognosis and treatment of cancer. (AU)
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