Sphingosine Kinase 1/S1P Axis in Endocrine Resistant Breast Cancer

内分泌耐药乳腺癌中的鞘氨醇激酶 1/S1P 轴

• 批准号: 9394135
• 负责人: Melissa Ann Maczis
• 金额: $ 3.61万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-10 至 2020-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9394135
• 关键词: Address; Binding; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Cancer Patient; Cancer Prognosis; Cell Nucleus; Cell membrane; Cessation of life; Clinical; Common Neoplasm; Cytosol; DNA Binding; Data; Dimerization; Disease; Distant Metastasis; Down-Regulation; Endocrine; Epidermal Growth Factor Receptor; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Event; Experimental Animal Model; Foundations; GPER gene; Gene Expression; Gene Targeting; Genomics; Growth; Growth Factor; Human; In Vitro; Ligand Binding Domain; Ligands; Link; MAPK3 gene; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane; Metastatic breast cancer; Neoplasm Metastasis; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Production; Progesterone Receptors; RNA Splicing; Recurrence; Regulation; Research; Resistance; Role; SPHK1 enzyme; Severities; Signal Pathway; Sphingolipids; Sphingosine; Tamoxifen; Testing; Therapeutic; Tissue Microarray; Transactivation; Transcriptional Activation Domain; Up-Regulation; Variant; Woman; base; cancer cell; cancer diagnosis; cancer type; dimer; experimental study; hormone therapy; improved; in vivo Model; innovation; malignant breast neoplasm; mortality; neutralizing antibody; non-genomic; novel; outcome forecast; receptor; response; sphingosine 1-phosphate; therapy resistant; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

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.

项目摘要 乳腺癌是女性中最常见的癌症，在美国有超过40，000名女性 每年死于转移性乳腺癌雌激素受体-α（ERα）及其配体17β-雌二醇（E2）发挥作用， 在乳腺癌中的重要作用。E2通过诱导ERα-受体基因组效应促进乳腺癌进展 通过结合其典型受体ERα66而导致乳腺癌阳性。然而，三阴性乳腺癌 （TNBC）缺乏ERα66，对激素治疗如他莫昔芬无反应。有人建议 新的剪接变体ERα36介导对E2的快速、非基因组应答。我们实验室以前的研究 表明E2激活鞘氨醇激酶1（SphK 1），后者产生具有生物活性的鞘脂代谢产物 1-磷酸鞘氨醇（S1 P）。分泌的S1 P反过来与其受体结合，导致下游信号传导 乳腺癌的进展和转移的重要途径和EGFR的反式激活。我的初步 结果使我提出了一个有趣的假设，即ERα36是E2-所需的膜受体。 介导的SphK 1激活和S1 P的快速分泌，其调节E2的关键非基因组效应 参与乳腺癌的激素治疗抵抗。我还认为SphK 1的表达增加 ERα36在转移性乳腺癌的原发性和获得性内分泌耐药中起重要作用。 了解负责从头和获得性激素治疗耐药的机制， 为更好的治疗提供线索。为了检验这一假设，将追求以下具体目标：（1） 建立参与TNBC细胞中SphK 1/S1 P轴活化的E2受体;（2）确定E2受体在TNBC细胞中的作用。 SphK 1/S1 P轴在内分泌耐药乳腺癌的体内外模型中的作用;（3）检测SphK 1/S1 P轴与内分泌耐药乳腺癌的相关性 SphK 1和ERα36表达与内分泌抵抗转移性乳腺癌患者预后的关系 该提案将确定SphK 1/S1 P轴在E2的非基因组效应中的作用，以及在E2的非基因组效应中的作用。 转移性乳腺癌内分泌抵抗的调节，为进一步研究奠定基础 关于SphK 1/S1 P通路作为规避内分泌的创新治疗选择的潜在靶向 抵抗力和改善患者预后。