Breaking Cancer Dormancy to Sensitize Dormant Breast Cancer Cells to Cytotoxic Chemotherapy
Abstract
Patients with breast cancer can develop recurrent metastatic disease with latency periods that range from years to decades. This pause can be explained by micrometastatic disseminated tumor cell (DTC) dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic and is clinically undetectable. Cancer dormancy remains an outstanding challenge for both clinicians and scientists. Recent findings have suggested that the cancer dormancy signaling program is characterized by low ERK:p38 MAPK signaling ratio and prolonged G0/G1 arrest, reminiscent of cancer stem cells, and is thought to be a major mechanism of resistance to conventional cytotoxic chemotherapy. Cancer EMT, which is thought to precede cancer dormancy, may also contribute directly to the cancer dormancy program through its ability to induce low ERK:p38 signaling ratio. The central role of p38 in cancer dormancy was recently demonstrated by the ability of p38 inhibitors (e.g. SB203580 or dominant negatives) to break dormancy and induce tumor growth, making it an attractive therapeutic target. Here we have proposed to test a novel therapeutic concept that breast cancer dormancy can be controlled by acutely forcing dormant cancer cells into rapid proliferation, thereby rendering them sensitive to killing by cytotoxic chemotherapy. We tested the feasibility of this innovative approach by inhibiting p38 MAPK before exposing cancer cells to cytotoxic chemotherapy. We used the MTB/TAN mouse model, a Tet-inducible activated human her2/Neu model, which produces PR/ER-negative and ErbB2-independent recurrent tumors (similar to human triple negative breast cancer) after withdrawal of doxycycline (deinduction). These recurrent tumors have all the characteristic of having undergone EMT and are relatively growth arrested and dormant.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2012
- Accession Number
- ADA567338
Entities
People
- David Tran
Organizations
- Washington University in St. Louis