Singleminded-2 in Mammary Gland and Breast Cancer

描述(由申请人提供)：Singlinded-2(Sim2)是bHLH-PAS蛋白家族的成员，通过调节神经元生长在中枢神经系统(CNS)的发育中发挥关键作用。SIM2最初是通过21号染色体上的定位克隆鉴定出来的，它与唐斯综合征(DS)的许多生理异常有关，是21三体的结果。DS患者的恶性疾病的发生模式是不同的，儿童时期白血病的风险非常高，一直持续到青年时期，实体瘤的风险下降了50%。女性的风险比男性低，这主要是因为没有乳腺癌，这被认为是21号染色体上肿瘤抑制基因的基因剂量效应的结果。虽然Sim2与重要的生物学功能有关，但人们对它在中枢神经系统以外的发育过程中的作用知之甚少，对其在癌症易感性中的作用更是知之甚少。我们的假设是Sim2的剪接变异体(Sim2S)是建立和/或维持正常乳腺上皮细胞生长和分化所必需的乳腺肿瘤抑制基因。这一假说的基本原理是基于初步数据，该数据表明Sim2s在原代人类乳房取消样本中减少，并在人类乳房上皮细胞和乳腺癌细胞系中差异表达。在侵袭性人乳腺癌细胞中重新表达Sim2S可降低细胞的增殖、非锚定生长和侵袭能力。此外，在处女小鼠乳腺移植模型中，Sim2s的缺失会导致异常的侧枝、增生性结节、基底膜的破坏和E-钙粘蛋白的下调。这一建议的具体目的是：1)利用基因敲除和转基因模型确定Sim2在乳腺发育中的作用；2)利用已建立的易患癌症的转基因小鼠，确定Sim2缺失和过表达对肿瘤发生的影响。这些结果将具有重要意义，因为它们将增加我们对以前未知的参与乳腺发育的途径的了解，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.