The Role of RB in the Therapeutic Response of Breast Cancer

The retinoblastoma tumor suppressor protein RB is functionally inactivated in the majority of human cancers, and lost in one third of all breast cancers. RB regulates G1S phase cell cycle progression and is a critical mediator of anti-proliferative signaling. Here the specific impact of RB loss on E2F-regulated gene expression, tumorigenic proliferation, and the response to distinct lines of therapy was interrogated in breast cancer cells. RB loss resulted in RBE2F target gene deregulation and accelerated tumorigenic proliferation, thereby demonstrating that even in the context of a complex tumor cell genome, RB status exerts significant control over proliferation. Furthermore, the loss of RB compromised the short-term cell cycle inhibition following DNA damage and anti-estrogen therapies. In the context of DNA damaging agents this bypass resulted in increased sensitivity to these agents in cell culture and xenograft models. In contrast, the bypass of anti-estrogen signaling resulted in continued proliferation and xenograft tumor growth in the presence of tamoxifen. These effects of RB loss were recapitulated by ectopic E2F expression, indicating that control of downstream target genes was an important determinant of the observed responses. Specific analyses of the RBE2F gene expression signature in 60 human patients indicated that deregulation of this pathway was associated with early recurrence following tamoxifen monotherapy. Thus, because the RB-pathway is a critical determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for directing therapy in the treatment of breast cancer.