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47854.pdf (4.2 MB)
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The role of non-muscle myosin IIa in HER2+ breast cancer tumorigenesis
Author Info
Alanazi, Samar
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1703173436523064
Abstract Details
Year and Degree
2023, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences.
Abstract
HER2 is over-expressed in around 15% to 20% of breast cancers. HER3 plays a critical role in HER2 mediated tumorigenesis. Increased HER3 transcription and protein levels occur upon inhibition of HER2. We aimed to identify proteins that bound to HER3 upon inhibition of the HER family with the pan-HER inhibitor neratinib in HER2+ breast cancer cells. Immunoprecipitation of HER3 followed by mass spectrometry experiments found non-muscle myosin IIA (NMIIA) increased upon neratinib treatment relative to vehicle DMSO treatment. MYH9 is the gene that encodes for the heavy chain of NMIIA. Breast cancer patients with high MYH9 were significantly associated with a shorter disease specific survival compared to patients with low MYH9 expression from the METABRIC cohort of patients. In addition, high MYH9 expression was associated with HER2+ tumors from this cohort. RT-qPCR and immunoblots of whole cell lysates of BT474 and MDA-MB-453 HER2+ breast cancer cells demonstrated elevated HER3 and NMIIA mRNA and protein levels upon neratinib treatment for 24 hours. To examine the role of NMIIA in HER2+ breast cancer, we modulated NMIIA levels in BT474 and MDA-MB-453 cells using doxycycline inducible shRNA targeting MYH9. MYH9 knockdown reduces HER3 protein levels and concomitant reduction in downstream P-Akt. In addition, loss of MYH9 suppresses cell growth, proliferation, migration, and invasion. Our data reveals that NMIIA regulates HER3 and loss of NMIIA reduces HER2+ breast cancer growth.
Committee
Joan Garrett, Ph.D. (Committee Chair)
Nimita Dave, PhD (Committee Member)
Susan Waltz, Ph.D. (Committee Member)
Nalinikanth Kotagiri, Ph.D. (Committee Member)
Pankaj Desai, Ph.D. (Committee Member)
Pages
47 p.
Subject Headings
Pharmaceuticals
Keywords
HER2
;
HER3
;
non-muscle myosin IIa
;
breast cancer
;
drug resistance
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Citations
Alanazi, S. (2023).
The role of non-muscle myosin IIa in HER2+ breast cancer tumorigenesis
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1703173436523064
APA Style (7th edition)
Alanazi, Samar.
The role of non-muscle myosin IIa in HER2+ breast cancer tumorigenesis.
2023. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1703173436523064.
MLA Style (8th edition)
Alanazi, Samar. "The role of non-muscle myosin IIa in HER2+ breast cancer tumorigenesis." Doctoral dissertation, University of Cincinnati, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1703173436523064
Chicago Manual of Style (17th edition)
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Document number:
ucin1703173436523064
Download Count:
62
Copyright Info
© 2023, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.