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 这项建议的主要目的是调查乳房的遗传调控网络。 发展和肿瘤发生。乳腺癌是最致命和可预防的疾病之一 女人。许多全面的研究表明，产次会影响患上 乳腺癌。这表明，与胎次相关的变化显著地重塑了乳房组织和细胞。 在小鼠身上，乳腺可以通过移植上皮成分来再生，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 癌症的发展。我们假设干细胞群体和特征的改变有助于 生命中乳腺的根本性变化。在之前提出的调查中，我们能够 建立几种用于分析乳腺干/祖细胞的转基因小鼠模型 不同的发展阶段。我们的研究表明，进化保守的Wnt途径是极其 在乳房发育的不同阶段对干细胞的调节至关重要。这一途径的异常调节 有助于乳腺的肿瘤性转化。之前的研究也发现了Gpr177 这是Wnt途径正常运作所必需的。这导致了一种假设，即互惠监管 Wnt和Gpr177是乳房发育和疾病所必需的。在这项提案中，我们将继续我们的 用几种复杂的小鼠遗传模型研究WNT的遗传回路。首先，我们将 确定Wnt/？-catenin信号在胚胎干细胞存活、增殖和分化中的作用 乳房发生和乳房重塑。接下来，我们将测试干细胞命运的改变是否有助于 WNT诱导的肿瘤形成。最后，我们将阐明相互调节的机制。 WNT和GPR177。小鼠的遗传分析将评估Wnt-Gpr177调节电路在 乳房发育和癌症。通过继续描绘Wnt介导的乳腺的细节 器官发生和发病机制，这一建议有可能推进我们的干细胞知识基础 生物学和癌症生物学，为治疗人类疾病带来了新的治疗策略。

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.