Bcl-2 induces cyclin D₁ promoter activity in human breast epithelial cells independent of cell anchorage

Cyclin D₁ expression is co-regulated by growth factor and cell adhesion signaling. Cell adhesion to the extracellular matrix activates focal adhesion kinase (FAK), which is essential for cyclin D₁ expression. Upon the loss of cell adhesion, cyclin D₁ expression is downregulated, followed by apoptosis in normal epithelial cells. Since bcl-2 prevents apoptosis induced by the loss of cell adhesion, we hypothesized that bcl-2 induces survival signaling complementary to cell adhesion-mediated gene regulation. In the present study, we investigated the role of bcl-2 on FAK activity and cyclin D₁ expression. We found that bcl-2 overexpression induces cyclin D₁ expression in human breast epithelial cell line MCF10A independent of cell anchorage. Increased cyclin D₁ expression in stable bcl-2 transfectants is not related to bcl-2-increased G₁ duration, but results from cyclin D₁ promoter activation. Transient transection studies confirmed anchorage-independent bcl-2 induction of cyclin D₁ promoter activity in human breast epithelial cell lines (MCF10A, BT549, and MCF-7). We provide evidence that bcl-2 induction of cyclin D₁ expression involves constitutive activation of focal adhesion kinase, regardless of cell adhesion. The present study suggests a potential oncogenic activity for bcl-2 through cyclin D₁ induction, and provides an insight into the distinct proliferation-independent pathway leading to increased cyclin D₁ expression in breast cancer.