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

描述(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属性，许多人认为这是耐药、复发和转移的罪魁祸首。对于异质性癌症，如乳腺癌，我们缺乏明确的治疗价值标记物。在乳腺癌的小鼠模型中，肿瘤干细胞的标志物干细胞抗原-1(SCA-1)与耐药和转移有关。SCA-1已被证明可以促进疾病进展，强调癌症干细胞在肿瘤发生中的重要性。我最近的工作对SCA-1的功能提供了重要的见解，证明了SCA-1与转化生长因子受体1结合，破坏转化生长因子受体复合体和导致肿瘤进展的Smad3信号转导。我还发现，在小鼠乳腺肿瘤中，SCA-1可以激活PI3K/AKT/ERK信号转导通路，并使PTEN失活。人乳腺癌存在转化生长因子-β信号转导障碍和PI3K通路激活，但缺乏小鼠Sca-1基因。我开始研究人类的SCA-1同源基因，一个Ly6基因家族是否调节转化生长因子-β和PI3K通路，以及它们是否与人类乳腺癌或癌症干细胞有关。对600多例原发性浸润性导管癌(TCGA，NCI)的肿瘤资料分析证实，与正常乳腺组织相比，浸润性导管癌中Ly6E和Ly6K基因的拷贝数增加和基因表达增强。我目前的数据表明，Ly6E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PI3K途径。相反，我发现Ly6K在ER阴性、抗雌激素耐药的癌细胞中过度表达，它扰乱了转化生长因子-β信号转导并激活了PI3K途径。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的方式传递给其人类亚型Ly6E和Ly6K。这项提议将检验我的假设，即Ly6K和Ly6E调节ER阴性和ER阳性肿瘤中的癌症干细胞，并调节转化生长因子β、PI3K和相关的信号节点，从而改变由此产生的肿瘤的表型和药物反应性。这项提议的结果将极大地促进我们对乳腺癌肿瘤进展和耐药机制的了解，并为我们提供新的治疗靶点和生物标志物。

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.