Role of p27 in tamoxifen response in breast cancer cell lines

Objective

The aim of the study was to experimentally point out the clinical results of p27 as a predictive factor for tamoxifen response in estrogen receptor-positive breast cancer cell lines. Normal human mammary epithelium expresses the CDK inhibitor p27, whereas p27 is downregulated in a fraction of breast cancer, associated with poor prognosis and aggressive features. Besides prognostic information, p27 has also been linked to prediction of treatment effects. In a randomized study, where patients were either treated with adjuvant tamoxifen or no treatment, we observed that low p27 was not associated with prognostic information but instead linked to poor treatment effect of the selective estrogen receptor modulator tamoxifen. In this study we evaluated the clinical data with an experimental approach using breast cancer cell lines.

Methods

Proliferation and cyclin D₁ protein levels were monitored after treatment with estrogen alone or together with tamoxifen, and p27 levels were modulated with siRNA transfection.

Results

Surprisingly, p27-downregulated MCF-7 cells responded to tamoxifen treatment but showed a decreased sensitivity to estrogen stimulation. For Cama-1 and T-47D cells there was no difference in estrogen or tamoxifen response in relation to p27. Cyclin D₁ protein levels corresponded to p27 in the siRNA experiments, validating the function of p27 in the model system.

Conclusion

Our results indicate that p27 was not required for mediating a tamoxifen effect in the tested cell lines but could function as an assembly factor essential for estrogen-induced proliferation. This potential assembly factor function for p27 might explain the observation in the primary breast cancer of a tamoxifen treatment predictive function for p27 in breast cancer.