Cyclin D and Cyclin E as Markers of Therapeutic Responsiveness in Breast Cancer

Abstract : There is now accumulating evidence to suggest that aberrant expression of cyclin D1 and cyclin E occurs in human breast cancer and overexpression of these two oncogenes is associated with poor prognosis in prirnary breast cancers. The role of cyclin D1 and cyclin E expression as markers of therapeutic responsiveness to cancer treatment was investigated using cell lines constitutively overexpressing cyclin D1 or cyclin E. In the first mstance, we tested whether overexpression of cyclin D1 or cyclin E may result in resistance to endocrine treatment in ER-positive T-47D human breast cancer cell lines using S-phase traction and colony-forming assays. Our findings indicated that overexpression of Cyclin D1 and to a lesser extent cyclin E confer resistance to progestin treatment. In contrast, overexpression of cyclin D1 or cyclin E appeared to interfere with the early cefl cycle effects of antiestrogen, but the long-term antiestrogen-induced growth inhibition remained effective in cyclin D1 or cyclin E overexpressing breast cancer. Dowuregulation of cyclin D1 levels by antiestrogen results in sensitivity of the cefls to the antiestrogen inhibition of cell proliferation in the long-term. Cyclin D1 overexpression leads to progestin resistance without sequestration of p27, indicating that regulation of cyclin D1 is a critical element of progestin inhibition in breast cancer cells. Colony-forming assays to date suggested that cyclin D1 or cyclin E had no impact on the sensitivity of breast cancer cells to chemotherapeutic agents including doxonibicin, methotrexate, 5-fluorouracil and paclitaxel which are commonly used in clinical breast cancer treatment. In the next 12 months, the significance of cyclin D1 or cyclin E as markers of responsiveness to endocrine and radiation treatment will be investigated in the clinical settings retrospectively.