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Defining the Mechanism of Action of Bromodomain and Extraterminal Inhibitors in Triple-Negative Breast Cancers

Brancato, Jennifer M
http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers have been extensively studied in a wide range of cancers, and several are being assessed in clinical trials for their safety and efficacy in both hematologic and solid tumors. However, we have a very limited understanding of the mechanism(s) of action of these drugs in cancer. It is important to determine how BET inhibitors (BETi) elicit their effects in order to identify patients who will benefit most from the therapy and to develop effective combination treatments that will provide durable responses and prevent resistance. Our studies centered on identifying the mechanism of action of BETi in triple-negative breast cancer (TNBC), an aggressive disease that lacks effective targeted therapies. We found that BETi induced multinucleation in TNBC due in part to the suppression of the critical mitosis regulators Aurora kinases A/B, and this was followed by apoptosis and senescence. The appearance of multinucleated cells coincided with the suppression of mitosis genes, increased mitotic timing, and the induction of apoptosis during mitosis or immediately following mitotic exit, all of which indicate that BETi induce mitotic catastrophe. We further discovered that LIN9, a member of the MuvB transcriptional regulatory complex, is a key mediator of BETi activity in TNBC. BETi disrupt binding of the BET protein BRD4 to the promoter of LIN9, leading to LIN9 downregulation, which in turn suppresses expression of mitosis genes and induces multinucleation. While the selectivity of BETi for cancer cells has been attributed to the dismantling of super-enhancers (SE) by BETi, our studies revealed that LIN9 and four other critical mitosis regulators lacked SEs, indicating BETi-induced mitotic catastrophe does not rely on the disruption of SEs. Finally, we discovered TNBCs may be particularly dependent on LIN9 expression. LIN9 is amplified/overexpressed in two-thirds of TNBCs, and high LIN9 expression is associated with poor survival. Together, these data reveal that tumors with amplified/overexpressed LIN9 such as TNBCs may be particularly responsive to BETi. They further suggest that an effective therapy to treat TNBC could be the combination of BETi and drugs that increase sensitivity to mitotic catastrophe.
Ruth Keri (Advisor)
Youwei Zhang (Committee Chair)
Goutham Narla (Committee Member)
Peter Scacheri (Committee Member)
Analisa DiFeo (Committee Member)
William Schiemann (Committee Member)
373 p.
Biomedical Research; Oncology; Pharmacology
Breast cancer; BET protein; BET inhibitor; LIN9; Aurora kinase; apoptosis; senescence; mitotic catastrophe

Recommended Citations

Citations

  • Brancato, J. M. (2018). Defining the Mechanism of Action of Bromodomain and Extraterminal Inhibitors in Triple-Negative Breast Cancers [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411

    APA Style (7th edition)

  • Brancato, Jennifer. Defining the Mechanism of Action of Bromodomain and Extraterminal Inhibitors in Triple-Negative Breast Cancers. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411.

    MLA Style (8th edition)

  • Brancato, Jennifer. "Defining the Mechanism of Action of Bromodomain and Extraterminal Inhibitors in Triple-Negative Breast Cancers." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1522842642716411

    Chicago Manual of Style (17th edition)

case1522842642716411
418
© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.