Author ORCID Identifier

0000-0003-0546-1570

Date of Graduation

8-2017

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dr. Naoto T. Ueno

Committee Member

Dr. Bedrich L. Eckhardt

Committee Member

Dr. Wendy A. Woodward

Committee Member

Dr. Varsha V. Gandhi

Committee Member

Dr. Peiying Yang

Abstract

Triple-negative (TNBC) and inflammatory (IBC) breast cancer are the most aggressive forms of breast cancer, accounting for 20% and 10% of cancer-related deaths, respectively. Among IBC cases, 30% are additionally classified with TNBC molecular pathology, a diagnosis that significantly worsens patient’s prognosis. The current lack of TNBC and IBC molecular understanding prevents the development of effective therapeutic strategies. To identify effective treatments, we explored aberrant apoptosis pathways and cell membrane fluidity as novel therapeutic targets.

We first identified an effective therapeutic strategy against TNBC and IBC by pro-apoptotic protein NOXA-mediated inhibition of the anti-apoptotic protein MCL1 following inhibition of histone deacetylases (HDAC) in combination with inhibition of the oncogenic MEK pathway. In breast cancer patients, low NOXA/high MCL1 tumor expression is indeed associated to poor survival outcomes, supporting the induction of NOXA expression, and subsequent inhibition of MCL1, for the treatment against TNBC and IBC.

Secondly, we investigated the role of an anti-inflammatory and non-toxic polyunsaturated fatty acid, eicosapentaenoic acid (EPA), for the development of a treatment strategy against TNBC and IBC. Through a synthetic-lethal siRNA high-throughput screen we identified inhibition of EPHA2, an oncogenic protein specifically associated to poor survival in TNBC patients, to be the top candidate that enhanced EPA cytotoxicity against TNBC and IBC cells. Though functional assays, we identified combination EPA and EPHA2-inhibition to be an effective therapeutic strategy involving the induction of cell death via modulation of cell membrane fluidity by ABCA1 inhibition-mediated intracellular cholesterol accumulation in triple-negative IBC cells.

In summary, here we provide robust preclinical evidence that supports the Phase I clinical development of combination HDAC and MEK inhibitors, and of EPA and EPHA2-inhibition, for the treatment of patients with TNBC and IBC.

Keywords

Triple-negative breast cancer, inflammatory breast cancer, HDAC inhibitor, MEK inhibitor, NOXA/PMAIP1, MCL1, eicosapentaenoic acid (EPA), EPHA2, ABCA1, membrane rigidity

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