This study provides a significant understanding of SphK1 inhibitors that can be used in the development of potential therapeutics against breast cancer.
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.
These findings suggest that export of S1P via ABCC1 functions in a malicious feed-forward manner to amplify the S1P axis involved in breast cancer progression and metastasis, which has important implications for prognosis of breast cancer patients and for potential therapeutic targets.<b>Implication:</b> Multidrug resistant transporter ABCC1 and activation of SPHK1 in breast cancer worsen patient's survival by export of S1P to the tumor microenvironment to enhance key processes involved in cancer progression.<i></i>.
Our data suggest that SPHK1 is involved in the development and progression of breast cancer and can serve as a potential predictive biomarker of distant metastasis and patient outcome.
The prognostic (overall survival, OS) and therapeutic (anti-endocrine therapy) co-contribution of IGF1R and SphK1 were investigated using breast cancer patient samples (n = 236) for immunohistochemistry to measure total and phosphorylated IGF1R and SphK1.
Previous studies suggested that S1P produced by sphingosine kinase 1 (SphK1) in breast cancer plays important roles in progression of disease and metastasis.
Sphingosine kinase 1 contributes to leptin-induced STAT3 phosphorylation through IL-6/gp130 transactivation in oestrogen receptor-negative breast cancer.
Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptor expression using quantitative real-time polymerase chain reaction (qRT-PCR) assay.
This is correlated with improved prognosis in patients who have a low HER1-3/SK1 expression ratio in their ER(+) breast cancer tumors compared to patients that have a high HER1-3/SK1 expression ratio.
Various studies in cell lines have previously demonstrated that sphingosine kinase 1 (SK1) and extracellular signal-regulated kinase 1/2 (ERK-1/2) interact in an estrogen receptor (ER)-dependent manner to influence both breast cancer cell growth and migration.
Sphingosine 1-phosphate (S1P), a potent sphingolipid mediator produced by sphingosine kinase isoenzymes (SphK1 and SphK2), regulates diverse cellular processes important for breast cancer progression acting in an autocrine and/or paracrine manner.
Prolactin upregulates sphingosine kinase-1 expression and activity in the human breast cancer cell line MCF7 and triggers enhanced proliferation and migration.