(82a) Tumor Microenvironment and Cancer Cell Dormancy

Breast cancer affects 1 in 8 women in the United States, and has a high risk of recurrence that can develop over the course of decades due to dissemination of cancer cells from the primary tumor to secondary sites. The time from the formation of the first micrometastasis to that of a clinically detectable macrometastasis is the rate-limiting step in metastasis and is called cancer dormancy. The mechanisms by which the host niche regulates tumor dormancy, or the characteristics of a dormant niche, are unknown. However, cells respond to the mechanical properties of their surrounding microenvironment. Common chemotherapeutic agents tamoxifen and 5-fluorouracil that are used in breast cancer treatment induce dormancy in breast cancer cells, but the underlying mechanisms and regulation by the microenvironment remain unclear. Here we investigated whether the physical microenvironment, specifically host tissue stiffness, affects the propensity of disseminated tumor cells to become dormant at secondary sites. We used a two-dimensional polyacrylamide (PA) gel-based culture model to investigate the effects of host tissue elastic modulus on drug-induced cancer cell dormancy. Breast cancer cells were cultured on PA gels of different stiffness to mimic the microenvironments of the normal mouse mammary gland and breast tumors respectively. We found that both tamoxifen and 5-fluorouracil induce dormancy in estrogen receptor-positive breast cancer cells as determined by immunofluorescence of Ki67 and flow cytometry analysis of propidium iodide staining. Drug-treated groups had a larger G0/G1 population, as well as reduced cyclin D1 and cylin A2 transcript levels compared to untreated controls. Surprisingly, cyclin-dependent kinase inhibitors p21 and p27 were also downregulated in the drug-treated groups. Our data suggest that tumor cells become dormant through regulation of cell cycle control proteins in a manner that differs from that of normal cells. Defining the characteristics of the microenvironment that control these mechanisms, and targeting the host niches that harbor dormant tumor cells before they form clinically detectable macrometastases, would pave the way for new treatments that will keep this incurable disease under control.