Fig. 9

Proposed model for differences observed in the Rb pathway in ER + and ER- tumors. The blue and orange colors of the Rb pathway members indicate increased or decreased expression relative to normal mammary gland derived from RNAseq data. Black framed white boxes include observed and white boxes framed in dashed frames contain proposed outcomes of Rb pathway status. A In B1/P/Rb_f ER-positive tumors, binding of T121 suppresses the activity of pRb, p107 and p130 proteins, releasing E2F inhibition and allowing progression of transcription of multiple genes involved in cell cycle regulation, including increased expression of cyclin E1, p107, CDK2 and CDK4. Inhibition of p130 activity in particular may result in release of a p130 complex from the Esr1 promoter that can lead to decrease in promoter methylation and thus to increased expression of ER. High ER levels, although not contributing to tumor proliferation directly via ER pathway, can still cross-activate additional pathways, such as PI3K/AKT/mTOR that were upregulated in tumors. B B1/P basal-like ER- tumors downregulated Rb1. Loss of pRb leads to release of E2F and to transcription of cell cycle regulating genes, including increased expression of cyclin D1, p130, and p16. Additional G2/M checkpoint genes can still be repressed by various complexes that p130 and p107 form with E2F proteins. Increased expression of p130 may lead to Esr1 promoter methylation through a p130 complex on Esr1 promoter, and thus to loss of ER expression