Cyclin D1 and Cyclin E as Markers of Therapeutic Responsiveness in Breast Cancer
Abstract
Cyclin Dl and cyclin E are overexpressed in approximately 43% and 30% of breast cancer and overexpression of these two oncogenes is associated with poor prognosis. To define the role of cyclin Dl and cyclin E expression as markers of therapeutic responsiveness, cell lines overexpressing cyclin Dl or cyclin E were produced. Constitutive overexpression of cyclin Dl in the range of 5 fold and cyclin E in the range of 3-6 fold were confirmed by Western blots. Measurement of S-phase fraction up to 72 hours and colony-forming assay up to 3 weeks of treatment with progestin and antiestrogen were assessed. Overexpression of cyclin Dl but not cyclin E induced progestin resistance in both short- and long-term treatment. Overexpression of cyclin Dl decreased sensitivity to antiestrogen inhibition at 24 and 48 hours, while overexpression of cyclin E was less pronounced. Antiestrogen treatment inhibited colony growth in cyclin Dl- or cyclin E-overexpressing cells following 3 weeks of treatment, but with a 2-2.3 fold decrease in sensitivity. Sensitivity to long-term antiestrogen was associated with downregulation of cyclin Dl protein levels. Colony-forming assay failed to demonstrate any effect of cyclin Dl or cyclin E overexpression on sensitivity to a range of chemotherapeutic agents including doxorubicin, methotrexate, 5-fluorouracil, paclitaxel. Ongoing translational research to assess the relationship between progestin/antiestrogen sensitivity and expression of cyclin Dl or p27 in the clinical setting will provide more insight into the usefulness of cyclin Dl in selecting the most efficacious endocrine therapy and its contribution to endocrine resistance in ER-positive breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2002
- Accession Number
- ADB282115
Entities
People
- Rina Hui
- Robert L. Sutherland
Organizations
- Garvan Institute of Medical Research