Singleminded-2 in Mammary Gland and Breast Cancer

描述（由申请人提供）：Singleminded-2（Sim 2）是bHLH-PAS蛋白家族的成员，通过调节神经元生长在发育中的中枢神经系统（CNS）中发挥关键作用。Sim 2最初是通过21号染色体上的定位克隆鉴定的，并且作为21三体的结果，其导致与唐斯综合征（DS）相关的许多生理异常。DS患者恶性疾病的发生模式不同，儿童期白血病的风险非常高，一直延伸到青年期，实体瘤减少50%。女性患乳腺癌的风险比男性低，主要是由于没有乳腺癌，这是因为21号染色体上的肿瘤抑制基因的基因剂量效应。虽然Sim 2与关键的生物学功能相关，但关于其在CNS以外的发育中的作用知之甚少，关于其在癌症易感性中的作用更是知之甚少。我们的假设是，Sim 2（Sim 2s）的剪接变体是建立和/或维持正常乳腺上皮细胞生长和分化所需的乳腺肿瘤抑制基因。这一假设的基本原理是基于初步数据，显示Sim 2s在原代人乳腺癌样品中减少，并在人乳腺上皮细胞和乳腺癌细胞系中差异表达。侵袭性人乳腺癌细胞中Sim 2s表达的再表达降低了增殖、锚定非依赖性生长和侵袭。此外，在处女小鼠乳腺移植模型中，Sim 2s的缺失导致异常的侧向分支、增生性结节、基底膜的破坏和E-钙粘蛋白的下调。本提案的具体目的是：1）使用基因敲除和转基因模型确定Sim 2s在乳腺发育中的作用; 2）使用已建立的癌症易感转基因小鼠研究Sim 2s缺失和过表达对肿瘤发生的影响。这些结果将是重要的，因为它们将增加我们对以前不知道参与乳腺发育的途径的理解，并为这种疾病的预防，诊断和治疗提供新的靶点。

DESCRIPTION (provided by applicant): Singleminded-2 (Sim2) is a member of the bHLH-PAS family of proteins and plays a key role in the developing central nervous system (CNS) by regulating neuron growth. Sim2 was initially identified by positional cloning on chromosome 21 and contributes to many of the physiological abnormalities associated with Downs Syndrome (DS) as a result of trisomy-21. The pattern of occurrence of malignant disorders in people with DS is different with a very high risk of leukemia in childhood extending into young adulthood and a 50% decrease in solid tumors. Women experience a lower risk than men, mainly due to the absence of breast cancer and this is though to be a result of a gene dosage effect of tumor suppressor genes on chromosome 21. Although Sim2 is associated with critical biological functions, very little is known regarding its role in development outside of the CNS, and even less is known about its role in cancer susceptibility. Our hypothesis is that a splice variant of Sim2 (Sim2s) is a mammary tumor suppressor gene required for establishing and/or maintaining normal mammary epithelial cell growth and differentiation. The rationale for this hypothesis is based on preliminary data showing that Sim2s is decreased in primary human breast cancel samples and differentially expressed in human breast epithelial cells and breast cancer cell lines. Re-expression of Sim2s expression in invasive human breast cancer cells decreases proliferation, anchorage-independent growth and invasion. In addition, loss of Sim2s in a virgin mouse mammary gland transplantation model results in abnormal lateral branching, hyperplastic nodules, breakdown of the basement membrane and down-regulation of E-cadherin. The specific aims of this proposal are to: 1) Determine the role of Sim2s in mammary gland development using knockout and transgenic models; 2) The effect of Sim2s loss and overexpression on tumorigenesis using established cancer prone transgenic mice. These results will be significant because they will increase our understanding of a pathway not previously known to be involved in mammary gland development and provide novel targets for preventive, diagnostic and therapeutic treatment of this disease.