Beckwitt, Colin
(2018)
Breast cancer metastatic dormancy and emergence, a role for adjuvant statin therapy.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Breast cancer is responsible for the most new cancer cases and is the second highest cause of cancer related deaths among women. Localized breast cancer is effectively treated surgically. In contrast, metastatic cancers often remain undetected as dormant micrometastases for years to decades after primary surgery. Emergence of micrometastases to form clinically evident metastases complicates therapeutic intervention, making survival rates poor. The often long lag time between primary tumor diagnosis and emergence of metastatic disease motivates the development or repurposing of agents to act as safe, long term adjuvants to prevent disease progression.
The statin drugs have been FDA approved for the treatment of hypercholesterolemia for three decades. Despite their well-studied effects on lipid homeostasis, statins feature beneficial pleiotropic effects on other organ systems and pathologies. Several epidemiological studies have demonstrated statins do not affect cancer incidence but do reduce breast cancer mortality. Previous in vitro work has demonstrated growth-suppressive and apoptosis-inducing effects of statins in tumor cell lines. However, the mechanisms and markers that contribute to statin’s suppressive effects on tumor cells remain unclear. We hypothesize that statins benefit cancer mortality by directly suppressing the outgrowth of dormant metastatic disease.
The data presented herein demonstrate that statins reduce tumor cell growth and survival, in part due to suppression of Ras and Akt signaling. Importantly, these effects are limited to the membrane-permeant lipophilic statins. In ex vivo and in vivo models of metastatic breast cancer, statins reduce the proliferation at the site of metastasis but not the primary tumor. Tumor cells expressing membrane E-cadherin are relatively more resistant to statin therapy, which implies that the clinical cancer mortality benefit observed is due to decreased outgrowth of dormant epithelial micrometastases into clinically evident mesenchymal macrometastases. These data motivate the further study of statins as safe, long term adjuvants to prevent emergent breast cancer. Moreover, these data recommend a therapeutic switch to lipophilic statins in breast cancer patients taking statins for other diseases. That statins selectively suppress metastatic but not primary tumor growth is promising for their use as safe, long term adjuvants to reduce recurrence and mortality from metastatic breast cancer.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
26 June 2018 |
| Date Type: |
Publication |
| Defense Date: |
22 May 2018 |
| Approval Date: |
26 June 2018 |
| Submission Date: |
18 June 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
355 |
| 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: |
Breast cancer, statin, metastasis, prenylation, Ras, Akt, dormancy, emergence |
| Date Deposited: |
26 Jun 2018 14:07 |
| Last Modified: |
29 Nov 2018 21:58 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/34651 |
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