Role of Changes in the Expression of Cyclins and Retinoblastoma Protein in the Development of Breast Cancer

摘要

Our studies, together with work carried out in other laboratories, have demonstrated that essentially all breast cancer cell lines and tumor tissues have defects of varying degrees in the cyclin D1-Rb-p16 regulatory pathway that controls cell cycle progression at the Gl/S boundary. The most common defect in cell lines we observe is the expression or overexpression of cyclin Dl in the presence of Rb, accompanied by a failure to express p16. Expression of moderate amounts of p16 in breast cancer cell lines with this type of defect suppresses the transformed properties of the cells, preventing growth in soft agar and blocking formation of tumors in nude mice, indicating that the fundamental defect in these cell lines appears to be the failure to express p16. The most common defect in breast tumor tissues is the overexpression of cyclin Dl in the presence of both Rb and pl6. The coexpression of Rb and p16 in these tumors suggests that abnormalities in cell cycle control may be minimal. However, in a subset of breast cancer cell lines also coexpressing Rb and p16, we have found that the fundamental defect in cell cycle regulation involves an insensitivity to the inhibitory actions of p16. These findings suggest the possibility that this unusual defect in cell cycle regulatory control may also be present in breast tumors which coexpress Rb and p16.