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The Retinoblastoma Tumor Suppressor Modifies the Therapeutic Response of Breast Cancer

Bosco, Emily E
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1147202417

Abstract Details

2006, PhD, University of Cincinnati, Medicine : Cell and Molecular Biology.
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.
Erik Knudsen (Advisor)
159 p.
Retinoblastoma Tumor Suppressor; Breast Cancer; E2F; Tamoxifen; anti-estrogen resistance; DNA damage; cell cycle checkpoint

Recommended Citations

Citations

  • Bosco, E. E. (2006). The Retinoblastoma Tumor Suppressor Modifies the Therapeutic Response of Breast Cancer [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1147202417

    APA Style (7th edition)

  • Bosco, Emily. The Retinoblastoma Tumor Suppressor Modifies the Therapeutic Response of Breast Cancer. 2006. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1147202417.

    MLA Style (8th edition)

  • Bosco, Emily. "The Retinoblastoma Tumor Suppressor Modifies the Therapeutic Response of Breast Cancer." Doctoral dissertation, University of Cincinnati, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1147202417

    Chicago Manual of Style (17th edition)

ucin1147202417
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© 2006, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.