Sphingosine Kinase 1/S1P Axis in Endocrine Resistant Breast Cancer

项目摘要 乳腺癌是女性中最常见的癌症，在美国有超过4万名女性 每年都死于转移性乳腺癌。雌激素受体-雌激素受体(ER-α，ER-α)及其配体17-雌二醇(17β-estadiol，E_2)的作用 在乳腺癌中的关键作用。E2通过在ER-α中诱导基因组效应促进乳腺癌进展 通过与其典型受体ERα66结合而呈阳性乳腺癌。然而，三重阴性乳腺癌 (TNBC)缺乏ERα66，对他莫昔芬等激素治疗没有反应。有人建议， 新的剪接变异体ERα36介导对E2的快速非基因组反应。我们实验室以前的研究 研究表明，雌二醇可以激活鞘氨醇激酶1(SphK1)，从而产生具有生物活性的鞘磷脂代谢物 鞘氨醇-1-磷酸(S1P)。分泌的S1P反过来与其受体结合，导致下游信号转导 EGFR通路和反式激活在乳腺癌进展和转移中的重要作用。我的初选 结果导致我提出了一个有趣的假设，即ERα36是E2-2所需的膜受体。 介导SphK1激活和S1P的快速分泌，调节E2的关键非基因组效应 参与乳腺癌激素治疗抵抗。我还认为SphK1的表达增加 ERα36在转移性乳腺癌的新发和获得性内分泌抵抗中起重要作用。 了解从头开始和获得性激素治疗抵抗的机制可能 为更好的治疗提供线索。为了验证这一假设，我们将追求以下具体目标：(1) 建立参与激活TNBC细胞SphK1/S1P轴的E2受体；(2)确定 SphK1/S1P轴在体内外内分泌耐药乳腺癌模型中的作用；(3)检验两者之间的相关性 SphK1和ERα36在内分泌耐药转移性乳腺癌患者中的表达及预后 这一建议将确定SphK1/S1P轴在E2的非基因组效应和在 内分泌抵抗在转移性乳腺癌中的调节作用，为进一步研究奠定基础 潜在靶向SphK1/S1P通路作为规避内分泌的创新治疗选择 抵抗和改善患者的预后。

Project Summary Breast cancer is the most commonly diagnosed cancer in women, and more than 40,000 women in the US die each year of metastatic breast cancer. The estrogen receptor-α (ERα) and its ligand 17β-estradiol (E2) play critical roles in breast cancer. E2 promotes breast cancer progression by eliciting genomic effects in ERα- positive breast cancers by binding to its canonical receptor ERα66. However, triple negative breast cancers (TNBC) lack ERα66 and do not respond to hormonal therapy such as tamoxifen. It has been suggested that the novel splice variant ERα36 mediates rapid, non-genomic responses to E2. Previous studies from our lab showed that E2 activates sphingosine kinase 1 (SphK1), which produces the bioactive sphingolipid metabolite sphingosine-1-phophate (S1P). Secreted S1P in turn binds to its receptors leading to downstream signaling pathways and transactivation of EGFR important for breast cancer progression and metastasis. My preliminary results led me to propose the intriguing hypothesis that ERα36 is the membrane receptor required for E2- mediated SphK1 activation and rapid secretion of S1P, which regulates key non-genomic effects of E2 involved in hormone therapy resistance of breast cancer. I also suggest that increased expression of SphK1 and ERα36 play an important role in de novo and acquired endocrine resistance in metastatic breast cancer. Understanding the mechanisms responsible for de novo and acquired hormonal therapy resistance may provide clues to better treatments. The following specific aims will be pursued to test this hypothesis: (1) Establish the E2 receptor involved in activation of the SphK1/S1P axis in TNBC cells; (2) Determine the role of SphK1/S1P axis in in vitro and in vivo models of endocrine resistant breast cancer; (3) Examine the correlation of expression of SphK1 and ERα36 in endocrine resistant metastatic breast cancer patients and prognosis. This proposal will establish the role of the SphK1/S1P axis in non-genomic effects of E2 and in the regulation of endocrine resistance in metastatic breast cancer and will lay the foundation for further research on potential targeting of the SphK1/S1P pathway as an innovative therapeutic option to circumvent endocrine resistance and improve patient outcome.