Thesis
Targeting Aurora A kinase (AURKA) and p21-activated kinase 1 (PAK1) in hormone receptor-positive breast cancer
Master of Science (M.S.), Drexel University
Nov 2016
DOI:
https://doi.org/10.17918/etd-7173
Abstract
Estrogen receptor [alpha] (ER[alpha]) is a hormone-dependent nuclear and cytoplasmic receptor that regulates many physiological processes, such as reproduction, bone integrity, cardiovascular health, cognition, and behavior. Activation of the ER-[alpha] pathway plays a crucial role in the development and progression of breast cancer, with 70-80% of breast tumors being positive for hormonal receptors and driven by ER-[alpha] signaling. Drugs targeting estrogen receptor, such as tamoxifen and fulvestrant, are used in the clinic to treat ER-[alpha] positive metastatic breast cancer. However, resistance to these therapies ultimately develops and represents a very significant clinical problem. One of the mechanisms of endocrine resistance is ligand-independent activation of ER-[alpha] by intracellular protein kinases. Mitotic kinase Aurora A kinase (AURKA) activates ER-[alpha] through phosphorylation at serine 167 and serine 305. P21-activated kinase 1 (PAK1), a kinase known as a key regulator of MAPK pathway and cytoskeleton remodeling, also modulates ER-[alpha] activation through phosphorylating serine 118 and serine 305. Phosphorylation at these serine residues has been correlated with the increased ER-[alpha] signaling and clinical outcomes. Herein, we show that pharmacological inhibition of AURKA and PAK1 synergistically decreases cell survival of both tamoxifen-resistant and tamoxifen-sensitive breast cancer cell lines in vitro. Further, in vivo study demonstrates that dual inhibition of AURKA and PAK1 limits growth of breast tumors and leads to increased apoptosis, especially in tamoxifen-resistant xenograft tumors. In vitro experiments show differentiated signaling patterns in tamoxifen-resistant and tamoxifen-sensitive breast cancer upon combination treatment. Taken together, these data suggest that targeting AURKA and PAK1 may be a promising therapeutic strategy for hormone receptor-positive breast cancer, especially in the settings of endocrine resistance.
Metrics
53 File views/ downloads
34 Record Views
Details
- Title
- Targeting Aurora A kinase (AURKA) and p21-activated kinase 1 (PAK1) in hormone receptor-positive breast cancer
- Creators
- Yayi Feng - DU
- Contributors
- Erica Golemis (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 7173; 991014632654604721