Technical Lead – Thea Tlsty, University of California, San Francisco
This project seeks to understand the mechanisms of explosive evolution and adaption under stress that can activate the forces for cancer progression and resistance to chemotherapy in mammalian cells.
We initiate our studies with the mammalian cell’s earliest response to stress. Applying fundamental principles of evolution dynamics, we examine stress-response transcription programs that have evolved in non-cancerous, pre-cancerous and cancerous human cells. Most cells of functioning tissue are programmed to arrest or die when exposed to DNA damage. In normal or “wild-type” human mammalian cells, the tumor suppressor protein p53 is the main mediator of this DNA damage response. This damage response can include programmed cell death (apoptosis) or cell cycle arrest. The abrogation of the DNA damage response is a hallmark of most cancers. Signals from the micro-environment of pre-malignant and malignant cells can modulate their response to stress and allow them to evade death.
We find that Transforming Growth Factor TGFbeta is involved in crosstalk with p53 signaling pathways in normal, pre-malignant and malignant human mammary cells. TGFbeta signaling attenuates the stress-induced p53-mediated apoptosis in pre-malignant and malignant mammary cells, but not in normal cells. TBFbeta signaling may contribute to breast cancer progression by protecting pre-malignant and metastatic cells from programmed cell death.