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, Steven Goodison, Ian Pagano, Kanani Hokutan, Rafael Peres, Lenora W.M. Loo, Brenda Hernandez, Aung Naing, Clayton D.K. Chong, Charles J. Rosser, Toshihiko Kawamori

Research output: Contribution to journalArticle

4 Citations (Scopus)

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

Fingerprint

Human Development
Epidermal Growth Factor
Breast Neoplasms
Claudin-2
Estrogen Receptors
sphingosine kinase
Neoplasms
Sphingolipids
Ceramides
Chemoprevention
Transgenic Mice
Carcinogenesis
Breast
Cell Proliferation
Gene Expression
Survival
Incidence

ASJC Scopus subject areas

  • Cancer Research

Cite this

Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model. / Shimizu, Yoshiko; Furuya, Hideki; Tamashiro, Paulette M.; Iino, Kayoko; Chan, Owen T.M.; Goodison, Steven; Pagano, Ian; Hokutan, Kanani; Peres, Rafael; Loo, Lenora W.M.; Hernandez, Brenda; Naing, Aung; Chong, Clayton D.K.; Rosser, Charles J.; Kawamori, Toshihiko.

In: Carcinogenesis, Vol. 39, No. 1, 01.01.2018, p. 47-55.

Research output: Contribution to journalArticle

Shimizu, Y, Furuya, H, Tamashiro, PM, Iino, K, Chan, OTM, Goodison, S, Pagano, I, Hokutan, K, Peres, R, Loo, LWM, Hernandez, B, Naing, A, Chong, CDK, Rosser, CJ & Kawamori, T 2018, 'Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model', Carcinogenesis, vol. 39, no. 1, pp. 47-55. https://doi.org/10.1093/carcin/bgx097
Shimizu, Yoshiko ; Furuya, Hideki ; Tamashiro, Paulette M. ; Iino, Kayoko ; Chan, Owen T.M. ; Goodison, Steven ; Pagano, Ian ; Hokutan, Kanani ; Peres, Rafael ; Loo, Lenora W.M. ; Hernandez, Brenda ; Naing, Aung ; Chong, Clayton D.K. ; Rosser, Charles J. ; Kawamori, Toshihiko. / Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model. In: Carcinogenesis. 2018 ; Vol. 39, No. 1. pp. 47-55.
@article{51e7dab0611e4c9c9a02cd5cfeacbbf7,
title = "Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model",
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.",
author = "Yoshiko Shimizu and Hideki Furuya and Tamashiro, {Paulette M.} and Kayoko Iino and Chan, {Owen T.M.} and Steven Goodison and Ian Pagano and Kanani Hokutan and Rafael Peres and Loo, {Lenora W.M.} and Brenda Hernandez and Aung Naing and Chong, {Clayton D.K.} and Rosser, {Charles J.} and Toshihiko Kawamori",
year = "2018",
month = "1",
day = "1",
doi = "10.1093/carcin/bgx097",
language = "English (US)",
volume = "39",
pages = "47--55",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Genetic deletion of sphingosine kinase 1 suppresses mouse breast tumor development in an HER2 transgenic model

AU - Shimizu, Yoshiko

AU - Furuya, Hideki

AU - Tamashiro, Paulette M.

AU - Iino, Kayoko

AU - Chan, Owen T.M.

AU - Goodison, Steven

AU - Pagano, Ian

AU - Hokutan, Kanani

AU - Peres, Rafael

AU - Loo, Lenora W.M.

AU - Hernandez, Brenda

AU - Naing, Aung

AU - Chong, Clayton D.K.

AU - Rosser, Charles J.

AU - Kawamori, Toshihiko

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85040778373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040778373&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgx097

DO - 10.1093/carcin/bgx097

M3 - Article

C2 - 28968647

AN - SCOPUS:85040778373

VL - 39

SP - 47

EP - 55

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 1

ER -