The Role of RB in the Therapeutic Response of Breast Cancer
Abstract
The retinoblastoma tumor suppressor protein (RB) is functionally inactivated in the majority of human cancers and nearly half of all breast cancers. RB participates in the growth regulation of breast cancer cells by controlling G1-S phase progression and mediating cell cycle arrest in response to DNA damage and anti-mitogenic signaling. Initially, estrogen-dependent breast tumors are often treated with anti-estrogens, such as tamoxifen or ICI, 182,780, while tumors that have become resistant are often treated with DNA-damaging agents such as ionizing radiation (IR) or cisplatin (CDDP). Although RB loss has been implicated in the bypass of both DNA damaging and anti-estrogenic therapeutic pathways exploration of the function of RB in breast cancer therapy has been limited. Here we develop stable clones to recapitulate RB loss in the MCF7 breast cancer model system using siRNA. In this model we demonstrate that acute RB loss in breast cancer cells results in downstream target deregulation. Additionally our data reveals that RB loss results in a growth advantage in vitro which is recapitulated in vivo as evidenced by accelerated tumor development in nude mouse xenografts. Interestingly RB-deficiency in these cells contributes to resistance to hormone ablation therapy in vitro and in vivo. RB knockdown cells are also resistant to DNA damage therapy ultimately leading to increased sensitivity both in vitro and in vivo. Taken together our data indicate that RB loss in breast cancer facilitates accelerated growth and cellular resistance to two major modes of breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2006
- Accession Number
- ADA448074
Entities
People
- Emily E. Bosco
Organizations
- University of Cincinnati