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DYNAMIC INTERACTIONS OF P53 AND C-ABL IN REGULATING BREAST CANCER PROGRESSION AND METASTASIS

Morrison, Chevaun Danielle
http://orcid.org/0000-0002-1685-3476
http://rave.ohiolink.edu/etdc/view?acc_num=case1481208229508494

Abstract Details

, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Breast cancer (BC) is the most diagnosed cancer amongst women in the United States and accounts for approximately 40,000 deaths per year. The nonreceptor kinase, c-Abl, regulates numerous aspects of normal mammary epithelial cell (MEC) physiology, however we found c-Abl expression to be downregulated during breast cancer progression. Importantly, the loss of c-Abl expression correlated with worse relapse free survival rates for BC patients. Interestingly, as BCs progress they lose sensitivity to the cytostatic actions of the pleiotropic cytokine, transforming growth factor ß (TGF-ß), as well, and instead utilize it for disease progression. These findings suggest that TGF-ß and c-Abl are both essential for the regulation of normal MECs. Overexpression of a constitutively active c-Abl mutant in aggressive triple negative BC (TNBC) cells attenuated oncogenic TGF-ß signaling and instead coupled TGF-ß to a novel Smad2/Smad1/5/8 pathway that reactivated p53 expression to induce a p21-dependent senescence. The novel c-Abl->TGF-ß->Smad2/Smad1/5/8->p53->p21 signaling axis robustly inhibited tumorigenesis of our aggressive TNBC xenograft model. Our findings further established that p53 and c-Abl become discordantly expressed in TNBCs. The ratio at which c-Abl and p53 are expressed predicts the levels of which the mitotic kinase, TTK, is expressed in TNBC. TTK is known to regulate the cellular localization of c-Abl in response to oxidative stress. This mechanism is particularly relevant because of the predominantly cytoplasmic localization c-Abl is found in certain TNBC cells and of the survival signaling c-Abl exerts while in the cytoplasm. Although, we found inhibition of TTK kinase activity or depletion of its expression sensitized TNBC cells to activated c- Abl, it was not due to alterations in the cellular localization of c-Abl. Instead, we found mutant p53 directly bound c-Abl in the cytoplasm and regulated its function in TNBCs. Finally, we found TNBC imatinib sensitivity is dependent on mutant p53 expression and that imatinib preferentially inhibits cytoplasmic c-Abl kinase activity while inducing its nuclear kinase activity and nuclear p53 expression. Mutation of p53, therefore, not only inactivates its own normal activities, but likely those of c-Abl as well, which provides insight into why c-Abl has divergent roles in regulating breast cancer progression.
William Schiemann (Advisor)
Mark Jackson (Committee Chair)
Thomas Egelhoff (Committee Member)
Alex Almasan (Committee Member)
Nathan Pennell (Committee Member)
Biology; Molecular Biology; Oncology
c-Abl; breast cancer; heterogeneity; triple-negative breast cancer; transforming growth factor beta; p53; p21

Recommended Citations

Citations

  • Morrison, C. D. (n.d.). DYNAMIC INTERACTIONS OF P53 AND C-ABL IN REGULATING BREAST CANCER PROGRESSION AND METASTASIS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1481208229508494

    APA Style (7th edition)

  • Morrison, Chevaun. DYNAMIC INTERACTIONS OF P53 AND C-ABL IN REGULATING BREAST CANCER PROGRESSION AND METASTASIS. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1481208229508494.

    MLA Style (8th edition)

  • Morrison, Chevaun. "DYNAMIC INTERACTIONS OF P53 AND C-ABL IN REGULATING BREAST CANCER PROGRESSION AND METASTASIS." Doctoral dissertation, Case Western Reserve University. Accessed MAY 02, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1481208229508494

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.