Author ORCID Identifier

https://orcid.org/0000-0002-8610-2475

Defense Date

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biochemistry

First Advisor

Sarah Spiegel, PhD

Second Advisor

Tomasz K. Kordula, PhD

Third Advisor

Jennifer Koblinski, PhD

Fourth Advisor

Paula D Bos, PhD

Fifth Advisor

Xianjun Fang, PhD

Abstract

Bioactive sphingolipid metabolite sphingosine-1‐phosphate (S1P) circulating levels have been implicated in breast cancer (BC) progression. BCs usually respond to 17β-Estradiol (E2) through canonical receptor ERα66 for genomic effects, however, E2 also triggers rapid, non-genomic responses. E2 has been shown to activate sphingosine kinase 1 (SphK1), increasing S1P for S1P receptors signaling important for BC. The E2 receptor activating SphK1 has not been identified. We demonstrate triple negative BC cells, expressing only novel ERα splice variant ERα36, E2-induced SphK1 activation for S1P secretion. Tamoxifen, first-line BC endocrine therapy, an ERα66 antagonist but ERα36 agonist, activates SphK1 and increases S1P secretion in tamoxifen resistant BCs. Furthermore, tamoxifen resistance correlates with increased SphK1 and ERα36 expression in patients. Therefore, targeting ERα36 and SphK1 axis may be a therapeutic option to circumvent endocrine resistance and improve patient outcome. In contrast, surprisingly, deletion or inhibition of the other isoenzyme that produces S1P, sphingosine kinase 2 (SphK2), shown to greatly increases circulating levels of S1P, markedly suppressed syngeneic triple-negative BC growth and pulmonary metastasis. In these lungs, immunosuppressive PMN-MDSCs and Tregs decreased and immunostimulant T effector, NK and M1 macrophages increased, creating a hostile microenvironment. Intriguingly, SphK2 inhibition or deletion increased lung ceramide and tumor suppressor p53 expression to decrease the genetic transformation of normal fibroblast to cancer-associated fibroblasts (CAF), restraining the CAF tumor-promoting secretome and creating an active anti-tumor microenvironment. This work highlights SphK2/p53 axis in stromal fibroblasts and suggests targeting SphK2 may pave way for development of novel targeted immunotherapeutics to boost anti-cancer immunity.

Rights

© Melissa A. Maczis

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

7-16-2020

Available for download on Tuesday, July 15, 2025

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