Interactions of PRL, Estrogen, and TFFa in Mammary Cancer

PRL、雌激素和 TFFa 在乳腺癌中的相互作用

• 批准号: 7094298
• 负责人: LISA M ARENDT
• 金额: $ 8.48万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094298
• 关键词: breast neoplasms; estrogens; human; model; neoplasm /cancer; role

DESCRIPTION (provided by applicant): This proposal describes a five year training program for the development of an academic career in biomedical sciences. This program will enhance critical skills for utilizing in vivo models as a tool for understanding complex human pathology. Dr. Linda Schuler, a recognized leader in the field of prolactin signaling, will mentor the principal investigator's scientific development. An advisory committee of highly-regarded scientists will provide guidance for this project as well as career advice. An estimate of 211,000 women in the United States will be diagnosed with invasive breast cancer this year. Although the focus for developing treatments has targeted hormonal signaling pathways, a critical gap exists in the knowledge of signaling cross talk among key factors that cooperate for dysregulated growth in this disease. Prolactin's (PRL) central role in mammary development, lactation, and involution has fueled interest in its signaling in breast cancer. The Schuler laboratory has generated transgenic mice that overexpress PRL under control of a mammary selective, non-hormonally responsive promoter, NRL. These mice develop mammary adenocarcinomas that are estrogen receptor alpha positive and negative, similar to human disease. Given the importance of estrogen and its receptor in the pathogenesis as well as treatment of this disease, this model is an excellent tool to study interactions between PRL and estrogen in disease development and progression. Another well-characterized mammary oncogene, transforming growth factor alpha (TGFa) has been correlated with estrogen receptor alpha negative breast tumors in humans and synergizes with PRL to induce mammary tumors in our transgenic model system. Using this model, we will investigate the hypothesis that circulating estrogen enhances the cooperative interaction of local mammary prolactin and TGFa to promote tumor development and progression. The specific aims include: 1) Examining the effect of post-pubertal ovarian estrogen on mammary lesion development, 2) Investigating the influence of estrogen on tumor progression once a lesion has developed, and 3) Identification of pathways of cooperative crosstalk among PRL, TGF alpha, and estrogen that may enhance carcinogenesis in vitro and in vivo. Together these studies will illuminate the cooperative roles of PRL, TGF alpha, and estrogen in the progression of breast cancer and could lead to useful diagnostic strategies and improved therapeutic targets.

描述（由申请人提供）： 该提案描述了一个为期五年的生物医学学术职业发展培训计划。该计划将增强利用体内模型作为理解复杂人类病理学工具的关键技能。 Linda Schuler 博士是催乳素信号传导领域公认的领导者，她将指导首席研究员的科学发展。由备受尊敬的科学家组成的咨询委员会将为该项目提供指导以及职业建议。 据估计，今年美国将有 211,000 名女性被诊断出患有浸润性乳腺癌。尽管开发治疗方法的重点是针对激素信号传导途径，但对导致这种疾病生长失调的关键因素之间的信号串扰的了解存在重大差距。催乳素 (PRL) 在乳房发育、哺乳和复旧过程中发挥着核心作用，这引起了人们对其在乳腺癌中信号传导的兴趣。舒勒实验室已经培育出了在乳腺选择性、非激素反应性启动子 NRL 控制下过度表达 PRL 的转基因小鼠。这些小鼠患上雌激素受体α阳性和阴性的乳腺癌，与人类疾病类似。鉴于雌激素及其受体在这种疾病的发病机制和治疗中的重要性，该模型是研究 PRL 和雌激素在疾病发生和进展中相互作用的绝佳工具。另一种特征明确的乳腺癌基因转化生长因子 α (TGFa) 与人类雌激素受体 α 阴性乳腺肿瘤相关，并与 PRL 协同作用，在我们的转基因模型系统中诱导乳腺肿瘤。使用该模型，我们将研究循环雌激素增强局部乳腺催乳素和 TGFa 的协同相互作用以促进肿瘤发生和进展的假设。具体目标包括：1) 检查青春期后卵巢雌激素对乳腺病变发展的影响，2) 研究病变发展后雌激素对肿瘤进展的影响，3) 识别 PRL、TGF 之间协同串扰的途径α和雌激素可能会增强体外和体内的致癌作用。这些研究将共同​​阐明 PRL、TGF α 和雌激素在乳腺癌进展中的协同作用，并可能带来有用的诊断策略和改进的治疗靶点。