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

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.

Ethnic differences in breast cancer in Hawai'i: age, stage, hormone receptor status, and survival.

Previous examinations of breast cancer and survival in Hawai'i's 5 major ethnic groups have found that Native Hawaiian women have the highest breast cancer mortality rates. Although ethnic disparities in survival are reduced when age and stage at diagnosis are controlled for statistically, prior studies could not explain ethnic variation in survival among women who were diagnosed at the same stage. We examined variations in breast tumor characteristics for a multiethnic sample of 4,583 women diagnosed in 1990-1997 by stage and age group and extended previous multivariate analyses by adding a new prognostic variable: estrogen receptor (ER) and progesterone receptor (PR) status. Logistic regression was used to examine the influence of age, stage, and hormone status on 5-year survival. With a few exceptions, greater proportions of Native Hawaiian women were diagnosed both in later stages of disease and at earlier ages compared to women of other ethnicities, and smaller proportions of Native Hawaiians survived 5 years post diagnosis in each stage and age group. Surprisingly, greater proportions of Native Hawaiian women in all age groups had ER/PR positive tumors, which is a prognostic indicator for better, not worse, survival. Native Hawaiian women had an increased risk of death and Japanese women had an increased chance of survival after controlling for age, stage, and ER/PR status. Future studies should examine other reasons for better survival of Japanese women and worse survival of Native Hawaiian women, including socioeconomic status, access to health insurance, adequacy of recommended screening frequency, co-morbid conditions, treatment appropriateness and compliance, and genetic markers of tumor aggressiveness.