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The Role of Sphingosine Kinase 1 in HER2/Neu-Induced Breast Tumorigenesis

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Item Summary

Title: The Role of Sphingosine Kinase 1 in HER2/Neu-Induced Breast Tumorigenesis
Authors: Shimizu, Yoshiko
Issue Date: Dec 2015
Publisher: [Honolulu] : [University of Hawaii at Manoa], [December 2015]
Abstract: Breast cancer is the most frequently diagnosed cancer and is second leading cause of death in U.S. Women. Human epidermal growth factor receptor 2 (HER2) is an oncogene that is overexpressed in approximately 30% of primary breast cancers and its amplification is associated with poor prognosis and aggressive phenotypes. Accumulating evidences suggest thataberrant regulation of sphingolipid pathway is frequently associated with multiple types of cancer, including breast cancer. In particular, elevation of SphK1 in the tumor has been associated with poor prognosis and outcome. In addition, in vitro study showed that S1P generated by SphK1 induces HER2 phosphorylation, which in turn activates extracellular signal regulated kinase signaling. While these limited findings provide important insights, the exact role of SphK1 in HER2-positive breast tumorigenesis remains unclear. Here, we aimed to define the role of SphK1 in HER2-positive breast tumorigenesis and investigate whether the pathway components are potential target for breast cancer prevention and therapies.
We first found that genetic deletion of SphK1 significantly inhibited breast tumor incidence and multiplicity in MMTV-neu transgenic mouse model. Interestingly, whole genome expression analysis revealed unique gene expression pattern associated with tumors from SphK1 deficient mice. Next, we found that the overexpression of SphK1 in human HER2-positive breast caner cell lines enhanced cell proliferation, colony formation, and migration/invasion, and drug resistance to cisplatin. Furthermore, overexpression of SphK1 led to increase in claudin 2 (CLDN2) expression (CLDN2 was identified as a key molecule that correlated with SphK1 expression) in HER2-positive breast caner cells. Lastly, we showed by using tissue microarray that the expressions of SphK1 and/or CLDN2 are higher in human HER2-positive breast tumors compared to matched adjacent normal tissue. Furthermore, high SphK1 and/or CLDN2 expressions were associated with high grade and ER-negativity. Interestingly, we found a strong correlation between SphK1 and CLDN2 expressions in tumors but not in normal tissues, confirming the results obtained in the animal study. Taken together, these findings suggest that SphK1 may play a pivotal role in HER2-positive breast carcinogenesis, and targeting SphK1 and/or CLDN2 may represent a novel approach for HER2-positive breast cancer chemoprevention and/or treatment.
Description: Ph.D. University of Hawaii at Manoa 2015.
Includes bibliographical references.
Appears in Collections:Ph.D. - Molecular Biosciences and Bioengineering

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