Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model

Yoshiko Shimizu, Hideki Furuya, Paulette M. Tamashiro, Kayoko Iino, Owen T.M. Chan, Steve Goodison, Ian Pagano, Kanani Hokutan, Rafael Peres, Lenora W.M. Loo, Brenda Hernandez, Aung Naing, Clayton D.K. Chong, Charles J. Rosser, Toshihiko Kawamori

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Abstract

Aberrant sphingolipid metabolism has been reported to promote breast cancer progression. Sphingosine kinase 1 (SphK1) is a key metabolic enzyme for the formation of pro-survival S1P from pro-apoptotic ceramide. The role of SphK1 in breast cancer has been well studied in estrogen receptor (ER)-positive breast cancer; however, its role in human epidermal growth factor 2 (HER2)-positive breast cancer remains unclear. Here, we show that genetic deletion of SphK1 significantly reduced mammary tumor development with reduced tumor incidence and multiplicity in the MMTV-neu transgenic mouse model. Gene expression analysis revealed significant reduction of claudin-2 (CLDN2) expression in tumors from SphK1 deficient mice, suggesting that CLDN2 may mediate SphK1's function. It is remarkable that SphK1 deficiency in HER2-positive breast cancer model inhibited tumor formation by the different mechanism from ER-positive breast cancer. In vitro experiments demonstrated that overexpression of SphK1 in ER-/PR-/HER2+ human breast cancer cells enhanced cell proliferation, colony formation, migration and invasion. Furthermore, immunostaining of SphK1 and CLDN2 in HER2-positive human breast tumors revealed a correlation in high-grade disease. Taken together, these findings suggest that SphK1 may play a pivotal role in HER2-positive breast carcinogenesis. Targeting SphK1 may represent a novel approach for HER2-positive breast cancer chemoprevention and/or treatment.

Original languageEnglish (US)
Pages (from-to)47-55
Number of pages9
JournalCarcinogenesis
Volume39
Issue number1
DOIs
StatePublished - Jan 1 2018

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Shimizu, Y., Furuya, H., Tamashiro, P. M., Iino, K., Chan, O. T. M., Goodison, S., Pagano, I., Hokutan, K., Peres, R., Loo, L. W. M., Hernandez, B., Naing, A., Chong, C. D. K., Rosser, C. J., & Kawamori, T. (2018). Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model. Carcinogenesis, 39(1), 47-55. https://doi.org/10.1093/carcin/bgx097