Sobek, Kathryn
(2013)
Regulation, Function, and Clinical Relevance of ABCG2 in Prostate Cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
ABCG2 is known to efflux folates and dihydrotestosterone, both of which are important for prostate tumor growth. Recently the Q141K variant of ABCG2, which decreases the function of ABCG2, was found to have an impact on survival time in prostate cancer (PCa) patients. In addition, ABCG2 may be involved in cellular resistance to docetaxel, a chemotherapeutic used to treat late-stage PCa. Because ABCG2 function appears to be correlated with survival times and may transport molecules important in prostate growth and cancer treatment, it is crucial to understand its expression, function, and regulation in PCa.
An observed CpG island in the ABCG2 promoter indicates the potential for regulation by DNA methylation. Accordingly, transcription of ABCG2 was increased after treatment with a DNA methyltransferase inhibitor. Furthermore, PCa cell lines grown in a folate deficient environment increased the expression of ABCG2, which was due to hypomethylation of the ABCG2 promoter.
Patients with recurrent PCa carrying the Q141K variant of ABCG2 had a significantly shorter time to PSA recurrence post-prostatectomy than patients carrying the wild-type allele. Transport studies showed that the Q141K variant expressing HEK293 cells retained more folic acid than their wild-type counterparts, and surprisingly, patients carrying the Q141K variant had decreased systemic folate levels. Furthermore, while it was known that docetaxel-treated PCa patients carrying the Q141K variant have a longer survival time, we found this is likely because ABCG2 plays a role in docetaxel efflux. PCa cell lines were highly resistant to forced expression of exogenous ABCG2. This was due in part to induced expression of two miRNAs known to repress ABCG2 in other cancer cell lines.
In conclusion, the Q141K variant appears to play opposing roles in prostate cancer. By decreasing folate efflux, intracellular folate levels and cell proliferation increase, but docetaxel treatment can increase tumor-cell drug sensitivity, which increases patient survival time. Our enhanced understanding of the varied docetaxel response among patients as well as evidence that ABCG2 is an as of yet unforeseen, major player in regulation of systemic folate levels may have implications in determining a personalized treatment plan for a cancer patient based on their ABCG2 genotype.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
17 December 2013 |
| Date Type: |
Publication |
| Defense Date: |
13 November 2013 |
| Approval Date: |
17 December 2013 |
| Submission Date: |
16 December 2013 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
119 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ABCG2, prostate cancer, docetaxel, folate, Q141K SNP, |
| Date Deposited: |
17 Dec 2013 14:20 |
| Last Modified: |
19 Dec 2016 14:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/20281 |
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