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The Role of Eukaryotic Translation Initiation Factor 4A1 in Breast Cancer Chemoresistance

Sridharan, Sangita
http://orcid.org/0000-0002-9164-9803
http://rave.ohiolink.edu/etdc/view?acc_num=mco1607040711704949

Abstract Details

2020, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Cancer Biology).
Chemoresistance is a major clinical concern in triple-negative breast cancer (TNBC) patients, leading to minimal residual disease and tumor relapse. Intrinsic chemoresistance is mediated by the surviving breast cancer stem-like cells (BCSCs) that self-renew and undergo multilineage differentiation to repopulate into a heterogeneous tumor. BCSCs are not only intrinsically chemo/radio resistant, but can also interconvert between BCSCs and bulk tumor cells. In addition to intrinsic therapy resistance, cancer cells can also acquire resistance when they are gradually exposed to therapy, which is the usual course of a treatment regimen. During this process, cancer cells continuously adapt and rewire or reprogram themselves and their microenvironment by upregulating drug transporter proteins and survival factors for their sustenance. Therefore, it is imperative to identify novel molecular targets and develop therapeutic strategies that could co-target BCSCs and bulk tumor cells to tackle both, intrinsic and acquired chemoresistance. Many oncogenic signaling pathways converge at the eukaryotic protein translation initiation machinery, the eIF4F complex which plays a key role in regulating the translatome. This complex plays a critical role in translation of several oncogenic mRNAs implicated in cellular proliferation, invasion, metastasis and chemoresistance. In our previous study, we demonstrated that the mRNA helicase eIF4A1 of the eIF4F complex, serves as a vulnerable node in inducing cell-death in TNBC cells. In our current study, we hypothesized that targeting eIF4A1 could be used as a strategy to overcome breast cancer chemoresistance. We developed two model systems; BCSCs and paclitaxel-resistant cells, reflective of intrinsic and acquired chemoresistance. Through pharmacological (Rocaglamide A) and genetic (CRISPR-Cas9) targeting of eIF4A1, we observed a statistically significant reduction in the self-renewal ability, pluripotency factors and drug transporter expression and a concurrent induction of cell death. Thus, our study demonstrated for the first time that targeting eIF4A1 is effective in targeting not only tumor cells, but also chemoresistant cells and BCSCs in vitro. Our research therefore sets up a stage to employ small molecule inhibitors against eIF4A1 in co-targeting strategies in vivo.
Dayanidhi Raman (Advisor)
Kathryn Eisenmann (Committee Member)
Saori Furuta (Committee Member)
Nagalakshmi Nadiminty (Committee Member)
Amit Tiwari (Committee Member)
193 p.
Biomedical Research
Triple-negative breast cancer; Chemoresistance; Breast cancer stem-like cells; eIF4A1; ABC drug transporters; Rocaglamide A

Recommended Citations

Citations

  • Sridharan, S. (2020). The Role of Eukaryotic Translation Initiation Factor 4A1 in Breast Cancer Chemoresistance [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1607040711704949

    APA Style (7th edition)

  • Sridharan, Sangita. The Role of Eukaryotic Translation Initiation Factor 4A1 in Breast Cancer Chemoresistance. 2020. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1607040711704949.

    MLA Style (8th edition)

  • Sridharan, Sangita. "The Role of Eukaryotic Translation Initiation Factor 4A1 in Breast Cancer Chemoresistance." Doctoral dissertation, University of Toledo, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=mco1607040711704949

    Chicago Manual of Style (17th edition)

mco1607040711704949
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This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.
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