Author ORCID Identifier

0000-0002-3907-9321

Date of Graduation

5-2018

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dihua YU, MD., PhD.

Committee Member

Anil K. Sood, MD.

Committee Member

Boyi Gan, PhD.

Committee Member

Dos D. Sarbassov, PhD.

Committee Member

Swathi Arur, PhD

Abstract

Distant metastasis is the primary cause of breast cancer–related mortality. To date, effective therapeutic drugs that target metastasis are still lacking. Triple negative breast cancer (TNBC) occurs in high frequency in young women and are more likely to recur and metastasize than are other breast cancer subtypes. Also, TNBC patients cannot benefit from currently available hormonal or targeted therapies, as they lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Thus, understanding the signaling pathways that promote TNBC metastasis and developing novel therapeutic approaches to target them are critical, in order to prolong the survival and improve the quality of life for these patients.

Aiming for fast clinical-translation, I performed bioinformatic analysis of patient-derived TCGA dataset to identify gene targets whose expressions are elevated in TNBC and which also have FDA-approved or in-pipeline pharmaceutical agents for repurposed intervention. Here, I found that sphingosine kinase 1 (SPHK1) was expressed at higher levels in TNBCs patients samples than in other breast cancer subtypes and high SPHK1 expression is associated with poor survival in TNBC patients. Also, TNBC cell lines have relatively higher expression of SPHK1 at both protein and mRNA levels compared to cell lines of other subtypes of breast cancer.

In this dissertation, I studied a role of SPHK1 in promoting TNBC progression and metastasis and identified a molecular mechanism by which SPHK1 promotes TNBC metastasis. Overall, this study identifies a targetable molecular axis which plays an important role in TNBC metastasis and provide an opportunity for fast repositioning of available therapeutics for treatment of TNBC metastasis.

Keywords

TNBC, Metastasis, SPHK1, Treatment of TNBC metastasis

Available for download on Friday, April 26, 2019

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