Genetic Regulatory Network in Mammary Gland Development and Tumorigenesis

标题 乳腺发育和肿瘤发生中的遗传调控网络 摘要 本研究的主要目的是研究乳腺癌的遗传调控网络， 发育和肿瘤发生。乳腺癌是最致命和最可预防的疾病之一， 妇女许多综合性研究表明，性别平等会影响遭受性虐待的机会。 乳腺癌这表明胎次依赖性改变显著重塑乳腺组织和细胞。 在小鼠中，乳腺可以通过移植上皮成分再生，这表明 乳腺干细胞的存在。它们的多能性进一步表明，乳腺干细胞参与了 癌症发展我们假设干细胞群体和特征的改变有助于 乳腺在生命中的根本变化。在之前提出的调查中，我们能够 开发几种转基因小鼠模型，用于分析乳腺干/祖细胞， 不同的发展阶段。我们的研究表明，进化保守的Wnt途径是非常重要的， 在乳房发育的不同阶段对干细胞调节至关重要。该途径的异常调节 有助于乳腺的肿瘤转化。以前的研究也发现了Gpr 177 这是Wnt通路正常运作所必需的。这导致了一个假设， Wnt和Gpr 177对乳腺发育和疾病至关重要。在这一建议中，我们将继续我们的 使用几种复杂的小鼠遗传模型研究Wnt的遗传电路。一是 在胚胎干细胞的存活、增殖和分化中定义Wnt/<$-catenin信号 乳房发育和乳房重塑。接下来，我们将测试干细胞命运的改变是否有助于 Wnt诱导的肿瘤发生。最后，我们将阐明相互调节的机制， Wnt和Gpr 177。小鼠中的遗传分析将评估Wnt-Gpr 177调节回路在小鼠中的需要。 乳腺发育和癌症。通过继续描述Wnt介导的乳腺癌的细节， 器官发生和发病机制，这一建议有可能推进我们的知识基础的干细胞 生物学和癌症生物学，导致治疗人类疾病的新的治疗策略。

Title Genetic Regulatory Network in Mammary Development and Tumorigenesis Abstract The primary objective of this proposal is to investigate the genetic regulatory network underlying mammary development and tumorigenesis. Breast cancer is one of the most deadly and preventable diseases among women. Many comprehensive studies have indicated that parity affects the chances of being inflicted with breast cancer. This suggests that parity-dependent alterations significantly remodel the breast tissues and cells. In mice, mammary glands can be regenerated by transplantation of epithelial components, suggesting the existence of mammary stem cells. Their pluripotency further implies that mammary stem cells are involved in cancer development. We hypothesize that alterations in the stem cell population and characteristics contribute to the fundamental changes of mammary glands in life. In the previously proposed investigation, we were able to develop several genetically modified mouse models for the analysis of mammary stem/progenitor cells at various developmental stages. Our studies indicate that the evolutionary conserved Wnt pathway is extremely crucial for stem cell regulation in different phases of mammogenesis. Aberrant regulation of this pathway contributes to the neoplastic transformation of the mammary gland. Previous study also identified Gpr177 which is required for proper functioning of the Wnt pathway. This led to a hypothesis that reciprocal regulation of Wnt and Gpr177 is essential for breast development and disease. In this proposal, we will continue our investigation on the genetic circuitry of Wnt using several sophisticated mouse genetic models. First, we will define Wnt/¿-catenin signaling in survival, proliferation and differentiation of stem cells during embryonic mammogenesis and mammary remodeling. Next, we will test if alterations of the stem cell fate contribute to the Wnt-induced tumorigenesis. Finally, we will elucidate the mechanism underlying the reciprocal regulation of Wnt and Gpr177. Genetic analysis in mice will assess the requirement of the Wnt-Gpr177 regulatory circuit in mammary development and cancer. By continuing to delineate the details of Wnt-mediated mammary organogenesis and pathogenesis, this proposal has potential to advance our knowledge base of stem cell biology and cancer biology, leading to novel therapeutic strategies for the treatment of human diseases.