Breast cancer sphingosine-1-phosphate is associated with phospho-sphingosine kinase 1 and lymphatic metastasis.
Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, has been implicated as a key regulatory molecule in cancer through its ability to promote cell proliferation, migration, angiogenesis, and lymphangiogenesis. Previous studies suggested that S1P produced by sphingosine kinase 1 (SphK1) in breast cancer plays important roles in progression of disease and metastasis. However, the associations between S1P and clinical parameters in human breast cancer have not been well investigated to date.



We determined levels of S1P and other sphingolipids in breast cancer tissue by electrospray ionization-tandem mass spectrometry. Associations between S1P levels and clinicopathologic features of the tumors were analyzed. Expression of phospho-SphK1 (pSphK1) in breast cancer tissues was determined by immunohistochemical scoring.



Levels of S1P in breast cancer tissues were significantly higher in patients with high white blood cell count in the blood than those patients without. S1P levels were lower in patients with human epidermal growth factor receptor 2 overexpression and/or amplification than those patients without. Furthermore, cancer tissues with high pSphK1 expression showed significantly higher levels of S1P than cancer tissues without. Finally, patients with lymph node metastasis showed significantly higher levels of S1P in tumor tissues than the patients with negative nodes.



To our knowledge, this is the first study to demonstrate that high expression of pSphK1 is associated with higher levels of S1P, which in turn is associated with lymphatic metastasis in breast cancer.
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan.
Junko
J
Tsuchida
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan. Electronic address: mnagahashi@med.niigata-u.ac.jp.
Masayuki
M
Nagahashi
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan.
Masato
M
Nakajima
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan.
Kazuki
K
Moro
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan.
Kumiko
K
Tatsuda
Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and the Massey Cancer Center, Richmond, Virginia.
Rajesh
R
Ramanathan
Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and the Massey Cancer Center, Richmond, Virginia; Breast Surgery, Roswell Park Cancer Institute, Buffalo, New York.
Kazuaki
K
Takabe
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan.
Toshifumi
T
Wakai
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008207:Lymphatic Metastasis; D008246:Lysophospholipids / Q000378:metabolism*; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism; D000099157:Sphingosine Kinase
D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
Breast cancer; HER2; Inflammation; Lymphatic metastasis; Phospho-sphingosine kinase 1; Sphingosine-1-phosphate