Effect of lipid mediator pumped out by ABC transporter to breast cancer microenvironment

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19055
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Yokohama City University
• Principal Investigator: Akimitsu Yamada 横浜市立大学, 医学研究科, 客員研究員 (90567603)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 乳癌 / ABC輸送体 / S1P / 癌微小環境

Outline of Final Research Achievements

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid mediator, has been implicated in regulation of many processes important for breast cancer progression. We demonstrated that overexpression of ABC transporter that efflux S1P in breast cancer cells enhanced S1P secretion, proliferation and migration of breast cancer cells. Implantation of these cells into the mammary fat pad of mice markedly enhanced tumor growth, angiogenesis and lymphangiogenesis with a concomitant increase in lymph node and lung metastases as well as shorter survival. Furthermore, patients with breast cancers that express both activated SPHK1 and ABC transporter have significantly shorter disease-free survival. These findings suggest that export of S1P via ABC transporter 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.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

本研究によって、脂質シグナル伝達物質S1Pが生成/排出のサイクルを介して乳癌微小環境に作用し乳癌の増悪に関与していることが示された．現在S1Pシグナルを標的とした治療薬として、S1P受容体修飾薬が，本邦では未承認であるが海外では免疫修飾薬として多発性硬化症に投与されており，潰瘍性大腸炎・関節リウマチなどに対する臨床試験が行われている．今後，S1Pシグナル標的治療が癌治療へ応用される可能性があり，本研究がその一助となることが期待される．