Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model. (11th September 2017)

• Record Type: Journal Article
• Authors: Shimizu, Yoshiko; Furuya, Hideki; Tamashiro, Paulette M; Iino, Kayoko; Chan, Owen T M; Goodison, Steve; Pagano, Ian; Hokutan, Kanani; Peres, Rafael; Loo, Lenora W M; Hernandez, Brenda; Naing, Aung; Chong, Clayton D K; Rosser, Charles J; Kawamori, Toshihiko
• Is Part Of: Carcinogenesis. Volume 39:Number 1(2018)
• Page Start: 47
• Page End: 55
• Publication Date: 2017-09-11
• Subjects: Carcinogenesis -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Periodicals; 616.994071
• DOI: 10.1093/carcin/bgx097
• Languages: English
• ISSNs: 0143-3334

Abstract

Abstract : This work shows that sphingosine kinase 1 (SphK1) deficiency inhibits human epidermal growth factor 2 (HER2)-positive breast carcinogenesis probably by regulating claudin-2. The results suggest that targeting SphK1 may represent a novel approach for HER2-positive breast cancer chemoprevention and/or treatment. 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.