Cell-Specific Responses to Chemotherapy Agents in Breast Cancer

Melissa A. Troester, Ph.D. and William K. Kaufmann, Ph.D.
University of North Carolina at Chapel Hill
T32ES07017, F32ES12374, P30ES10126, and U19ES11329

Background: Microarray gene expression profiling has recently been used to identify specific subtypes of breast cancer tumors that originate in different cell types and show differences in patient outcome. Breast tumors respond variably to chemotherapeutic agents such as doxorubicin and 5-fluorouracil and the responses are variable between patients as well. This team of NIEHS-supported scientists performed a series of microarray experiments to gain insight into the differing responses of different types of tumors to chemotherapeutic agents.

Advance: Four different breast cancer cell line cultures from two different cell types (basal and luminal epithelial cells) were treated with doxorubicin and 5-florouracil. Changes in gene expression were determined using microarray analyses. The overarching response in each of the cell lines was a general stress response, but distinct expression patterns were observed. Luminal cell lines tended to repress cell cycle-regulated genes and other genes involved in cellular proliferation. On the other hand, basal cell lines repressed genes involved in differentiation. The in vitro responses were then compared to expression responses in actual breast tumors sampled before and after treatment with the two drugs. The in vivo data matched well with the in vitro data with the cell-type-specific responses being very similar.

Implication: The similarity between the in vivo and in vitro response has implications for understanding the biological responses to the chemotherapeutic agents. These results may also help to identify new agents for treatment of breast cancer. In addition, the specific mechanisms of action of doxorubicin and 5-flurouracil may be evident in a subset of genes. Subsequent analyses will attempt to identify these specific genes.

Citation: Troester MA, Hoadley KA, Sorlie T, Herbert BS, Borresen-Dale AL, Lonning PE, Shay JW, Kaufmann WK, Perou CM. Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 2004 Jun 15;64(12):4218-26.