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The Retinoblastoma Tumor Suppressor Modifies the Therapeutic Response of Breast Cancer
| Title: | The Retinoblastoma Tumor Suppressor Modifies the Therapeutic Response of Breast Cancer |
| Author: | Bosco, Emily E |
| Description: | Abstract: The retinoblastoma tumor suppressor (RB) is functionally inactivated in the majority of human cancers, and nearly half of all breast cancers. Here, we investigate the consequence of RB loss on the response to DNA damage and anti-estrogenic therapies used in the treatment of breast cancer. Initially, we demonstrate that downstream RB targets are severely mis-regulated following acute deletion in adult primary cells causing abrogation of the DNA damage checkpoint and consequently, accumulation of secondary DNA lesions upon treatment with chemotherapeutics. Additionally, we found that RB modifies the DNA repair response in adult primary fibroblasts, such that RB-deficient cells are able to repair UV-induced lesions at an accelerated rate. These initial studies reveal that RB loss in primary cells modifies the response to DNA damage by promoting aberrant replication and inappropriately accelerating repair, both of which may ultimately sensitize cells to DNA damaging therapies. To specifically recapitulate RB loss in breast cancer, we directed shRNA against RB in MCF7 cells. RB-deficiency resulted in RB/E2F 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 anti-estrogen, cisplatin, and ionizing radiation 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 reiterated by ectopic E2F expression, indicating that control of downstream target genes was important for the observed responses. Specific analyses of the RB/E2F 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 determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for informing therapy in the treatment of breast cancer. |
| Permanent Link: |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1147202417
http://hdl.handle.net/2374.OX/10597 |
| Date: | 2006 |
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