Role of Ly6 genes in estrogen receptor positive and negative breast cancer

Ly6基因在雌激素受体阳性和阴性乳腺癌中的作用

• 批准号: 8637444
• 负责人: Geeta Upadhyay
• 金额: $ 20.29万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637444
• 关键词: Affect; Antigens; Binding; Biological Markers; Breast Cancer Cell; CD44 gene; Cancer Patient; Cancer cell line; Cell physiology; Cells; Clinical; Complex; Data; Data Analyses; Disease Progression; Drug resistance; Epithelial; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogen receptor positive; Evolution; Family; Future; Gene Expression; Gene Targeting; Gene-Modified; Genes; Growth; Heterogeneity; Homologous Gene; Human; Knowledge; Link; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mesenchyme; Molecular; Mus; Nature; Neoplasm Metastasis; Normal Cell; Outcome; PI3K/AKT; PTEN gene; Pathway interactions; Pharmaceutical Preparations; Phenotype; Prognostic Marker; Property; Protein Isoforms; Recurrence; Research; Resistance; Role; Sampling; Signal Transduction; Stem cells; Taxane Compound; Testing; The Cancer Genome Atlas; Therapeutic; Universities; Validation; Work; anticancer research; cancer cell; cancer stem cell; cohort; drug sensitivity; infiltrating duct carcinoma; insight; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; overexpression; patient oriented; prognostic; protein expression; public health relevance; receptor; role model; taxane; triple-negative invasive breast carcinoma; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Current challenges of cancer research focus on understanding the stem cell-like properties of a cancer cell, which many believe are responsible for drug resistance, recurrence and metastasis. We lack definite markers of therapeutic value in cancers of heterogeneous nature such as breast cancer. In mouse models of breast cancer a marker of cancer stem cells Stem cell antigen-1 (Sca-1) has been associated with drug resistance and metastasis. Sca-1 has been shown to enhance disease progression, emphasizing the importance of cancer stem cells in tumorigenesis. My recent work has provided significant insight into Sca-1 function, demonstrating that Sca-1 binds to TGF receptor 1 to disrupt the TGF-¿ receptor complex and Smad3 signaling leading to tumor progression. I also found that Sca-1 could activate PI3K/AKT/ERK signaling and inactivate PTEN in mouse mammary tumors. Human breast cancers show disruption of TGF-¿ signaling and activation of PI3K pathway but they lack murine Sca-1 gene. I set out to see if human homologues of Sca-1, a family of Ly6 genes regulate TGF-¿ and PI3K pathways and if they are relevant to human breast cancer or cancer stem cells. Oncomine data analysis on more than 600 primary invasive ductal carcinomas (TCGA, NCI), confirms a gain in copy number and increase in gene expression of Ly6E and Ly6K in invasive ductal carcinomas in comparison to normal breast tissue. My current data indicates that Ly6E is overexpressed in estrogen receptor alpha (ER) positive, antiestrogen sensitive breast cancer cells and it activate PI3K pathway. In contrast, I found that Ly6K is over expressed in ER negative, antiestrogen resistant cancer cells and it disrupts TGF-¿ signaling and activate PI3K pathway. This suggests that the signal transduction and growth-promoting phenotype of Sca-1 is passed on to its human isoforms Ly6E and Ly6K during evolution in gene specific manner. This proposal will test my hypothesis that Ly6K and Ly6E regulate cancer stem cells in ER negative and ER positive tumors and regulate TGF-¿, PI3K, and related signaling nodes, thereby altering the phenotype and drug responsiveness of resultant tumors. The outcome of this proposal will significantly advance our knowledge of mechanisms of tumor progression and drug resistance in breast cancer and present us with new therapeutic targets and biomarkers.

描述（由申请人提供）：目前癌症研究的挑战集中在了解癌细胞的干细胞样特性，许多人认为这是耐药性，复发和转移的原因。 我们缺乏对异质性癌症（如乳腺癌）具有治疗价值的明确标志物。 在小鼠乳腺癌模型中，癌症干细胞标志物干细胞抗原-1（Sca-1）与耐药性和转移有关。 Sca-1已被证明可以促进疾病的进展，强调了癌症干细胞在肿瘤发生中的重要性。 我最近的工作为Sca-1的功能提供了重要的见解，表明Sca-1与TGF-1受体结合，破坏TGF-1受体复合物和Smad 3信号传导，导致肿瘤进展。 我还发现Sca-1可以激活小鼠乳腺肿瘤中的PI 3 K/AKT/ERK信号转导和抑制PTEN。 人类乳腺癌显示TGF-β信号传导的破坏和PI 3 K通路的激活，但它们缺乏鼠Sca-1基因。 我开始研究Sca-1的人类同源物，Ly 6基因家族是否调节TGF-β和PI 3 K通路，以及它们是否与人类乳腺癌或癌症干细胞有关。 对超过600例原发性浸润性导管癌（TCGA，NCI）的Oncomine数据分析证实了与正常乳腺组织相比，浸润性导管癌中Ly 6 E和Ly 6 K的拷贝数增加和基因表达增加。 我目前的数据表明，Ly 6 E在雌激素受体α（ER）阳性、抗雌激素敏感的乳腺癌细胞中过表达，并激活PI 3 K通路。 相反，我发现Ly 6 K在ER阴性、抗雌激素抗性癌细胞中过度表达，它破坏TGF-β信号传导并激活PI 3 K通路。 这表明Sca-1的信号转导和促生长表型在进化过程中以基因特异性方式传递给其人类亚型Ly 6 E和Ly 6 K。 该提案将验证我的假设，即Ly 6 K和Ly 6 E调节ER阴性和ER阳性肿瘤中的癌症干细胞，并调节TGF-β，PI 3 K和相关信号节点，从而改变所得肿瘤的表型和药物反应性。 该提案的结果将大大提高我们对乳腺癌肿瘤进展和耐药性机制的认识，并为我们提供新的治疗靶点和生物标志物。