Woodcock, Chen-Shan
(2017)
Therapeutic Potential of Electrophilic Nitro-Oleic Acid for The Treatment of Triple-Negative Breast Cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Triple negative breast cancer (TNBC) comprises ~20% of all breast cancers and is the most aggressive breast cancer subtype. Devoid of expression of the estrogen and progesterone receptors, along with the receptor tyrosine kinase ERB2 (HER2) that defines most mammary cancers, there are no targeted therapies for patients with TNBC. This, combined with a high metastatic rate and a lower 5-year survival rate than for other breast cancer phenotypes, means there is significant unmet need for new therapeutic strategies.
Herein, the anti-neoplastic effects of the electrophilic fatty acid nitroalkene derivative, 10-nitro-octadec-9-enoic acid (nitro-oleic acid, NO2-OA), were investigated in multiple preclinical models of TNBC. NO2-OA reduced TNBC cell growth and viability in vitro, attenuated TNFα-induced TNBC cell migration and invasion and inhibited the tumor growth of MDA-MB-231 TNBC cell xenografts in the mammary fat pads of female nude mice. The upregulation of these aggressive tumor cell growth, migration and invasion phenotypes is mediated in part by the constitutive activation of proinflammatory nuclear factor kappa B (NF-κB) signaling in TNBC. NO2-OA inhibited TNFα-induced NF-κB transcriptional activity in human TNBC cells and suppressed downstream NF-κB target gene expression, including the metastasis-related proteins intercellular adhesion molecule-1 (ICAM-1) and urokinase-type plasminogen activator (uPA).
The mechanisms accounting for NF-κB signaling inhibition by NO2-OA in TNBC cells were multifaceted, as NO2-OA a) inhibited the inhibitor of NF-κB subunit kinase β phosphorylation and downstream inhibitor of NF-κB degradation, b) alkylated the NF-κB RelA protein to prevent DNA binding and c) promoted RelA polyubiquitination and proteasomal degradation. Comparisons with nontumorigenic human breast epithelial MCF-10A cells revealed that NO2-OA more selectively inhibited TNBC function. This was attributed to greater extents of multi-drug resistance protein-1 (MRP1) expression and greater MRP1-mediated efflux of NO2-OA glutathione conjugates in MCF-10A cells. Blocking MRP1 transporting activity by inhibitor probenecid sensitized MCF-10A cells to NO2-OA similar to its effect on TNBC cells, indicating that MRP1-mediated efflux can profoundly attenuate the NO2-OA biological activity in MCF-10A cells. This dissertation study will be an important illustration of how NO2-OA inhibits TNBC tumor development and its elucidation may have significant impact for the improvement of pharmacological therapies.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
19 December 2017 |
| Date Type: |
Publication |
| Defense Date: |
11 December 2017 |
| Approval Date: |
19 December 2017 |
| Submission Date: |
13 December 2017 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
144 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Pharmacology and Chemical Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Fatty acid nitroalkenes; Triple-negative breast cancer; NF-kappaB |
| Date Deposited: |
19 Dec 2017 20:18 |
| Last Modified: |
19 Dec 2022 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33604 |
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