Loss of sphingosine kinase 1 increases lung metastases in the MMTV-PyMT mouse model of breast cancer.

Fabiola N Velazquez,Lina M Obeid,Yusuf A Hannun,Ashley J Snider,Leiqing Zhang,Valentina Viscardi,Carolena Trocchia,Tiffany Seagroves

doi:10.1371/journal.pone.0252311

Fabiola N Velazquez, Lina M Obeid + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0252311

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Journal: PloS one	Publication Date: May 27, 2021
Citations: 1	License type: CC BY 4.0

Affiliation: Stony Brook University, University of Arizona

Abstract

Breast cancer is a very heterogeneous disease, and ~30% of breast cancer patients succumb to metastasis, highlighting the need to understand the mechanisms of breast cancer progression in order to identify new molecular targets for treatment. Sphingosine kinase 1 (SK1) has been shown to be upregulated in patients with breast cancer, and several studies have suggested its involvement in breast cancer progression and/or metastasis, mostly based on cell studies. In this work we evaluated the role of SK1 in breast cancer development and metastasis using a transgenic breast cancer model, mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT), that closely resembles the characteristics and evolution of human breast cancer. The results show that SK1 deficiency does not alter tumor latency or growth, but significantly increases the number of metastatic lung nodules and the average metastasis size in the lung of MMTV-PyMT mice. Additionally, analysis of Kaplan-Meier plotter of human disease shows that high SK1 mRNA expression can be associated with a better prognosis for breast cancer patients. These results suggest a metastasis-suppressing function for SK1 in the MMTV-PyMT model of breast cancer, and that its role in regulating human breast cancer progression and metastasis may be dependent on the breast cancer type.

Highlights

Of all types of cancer, breast cancer is the most common type among women
In order to define the role of Sphingosine kinase 1 (SK1) in breast cancer in an in vivo model of spontaneous generation of breast tumors, female MMTV-PyMT SK1-/- mice were generated with MMTV-PyMT SK1+/+ used as controls
The results obtained in this study demonstrate that SK1 deficiency does not participate in tumor latency and growth in the MMTV-PyMT mouse breast cancer model, and unexpectedly increases lung metastasis in this model

Summary

Introduction

Of all types of cancer, breast cancer is the most common type among women. In 2018, breast cancer had an incidence of 11.6% among all types of cancer, accounting for 6.5% of mortalities worldwide [1]. In the United States, breast cancer incidence rate has increased by 0.3% per year over the most recent 5-year period (2012–2016), but the rate of death has dropped 40% from 1989 to 2017 [2]; a decline that can be explained by advancements in early screening and therapy [3]. Breast cancer treatment is based on the receptor status of the tumor, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor. The main breast cancer molecular subtypes are termed Luminal A (ER+/PR+/HER2-/low Ki-67); Luminal B (ER+/ PR+/HER2-/+/high Ki-67); HER2-overexpression (ER-/PR-/HER2+) and basal/triple negative breast cancers (TNBCs) (ER-/PR-/HER2-) [4]

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