Interactions of PRL, Estrogen, and TFFa in Mammary Cancer

描述（由申请人提供）： 该提案描述了一个为期五年的培训计划，以发展生物医学科学的学术生涯。该计划将提高利用体内模型作为理解复杂人类病理学的工具的关键技能。琳达舒勒博士是催乳素信号领域公认的领导者，她将指导主要研究者的科学发展。一个由德高望重的科学家组成的咨询委员会将为这个项目提供指导和职业建议。 据估计，今年美国将有21.1万名妇女被诊断出患有浸润性乳腺癌。虽然开发治疗的重点是针对激素信号传导途径，但在这种疾病中合作失调生长的关键因素之间的信号传导串扰的知识存在着关键的差距。催乳素（PRL）在乳腺发育、泌乳和退化中的中心作用激发了人们对其在乳腺癌中的信号传导的兴趣。舒勒实验室已经产生了在乳腺选择性、非乳腺反应性启动子NRL控制下过表达PRL的转基因小鼠。这些小鼠发展为雌激素受体α阳性和阴性的乳腺腺癌，类似于人类疾病。鉴于雌激素及其受体在该病的发病机制和治疗中的重要性，该模型是研究PRL和雌激素在疾病发展和进展中相互作用的极好工具。另一种充分表征的乳腺癌基因转化生长因子α（TGF α）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TGF α的协同相互作用以促进肿瘤发展和进展的假设。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）一旦病变发展，研究雌激素对肿瘤进展的影响，和3）鉴定PRL、TGF α和雌激素之间的协同串扰途径，其可以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，并可能导致有用的诊断策略和改进的治疗靶点。

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.