Interactions of PRL, Estrogen, and TFFa in Mammary Cancer

描述(由申请人提供)： 这项建议描述了一项五年的培训计划，旨在发展生物医学科学的学术生涯。这项计划将加强关键技能，利用活体模型作为工具，理解复杂的人类病理。Linda Schuler博士是催乳素信号领域公认的领导者，她将指导首席研究员的科学发展。一个由备受尊敬的科学家组成的顾问委员会将为该项目提供指导，并提供职业建议。 据估计，今年美国将有21.1万名女性被诊断出患有浸润性乳腺癌。尽管开发治疗的重点是针对荷尔蒙信号通路，但在与这种疾病的失调生长协同作用的关键因素之间，对信号串扰的认识存在着关键的差距。催乳素(PRL)在乳腺发育、哺乳和退化中的核心作用引起了人们对其在乳腺癌中的信号转导的兴趣。舒勒实验室已经产生了在乳腺选择性非激素反应启动子NRL的控制下过度表达PRL的转基因小鼠。这些小鼠患上雌激素受体α阳性和阴性的乳房腺癌，类似于人类疾病。鉴于雌激素及其受体在本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发展过程中相互作用的极佳工具。在我们的转基因模型系统中，另一个特征很好的乳腺癌基因-转化生长因子α(TGFa)已经与雌激素受体α阴性的人类乳腺肿瘤相关，并与PRL协同诱导乳腺肿瘤。利用这个模型，我们将研究循环雌激素增强局部乳腺催乳素和TGFa的协同作用以促进肿瘤发生和进展的假说。其具体目的包括：1)检测青春期后卵巢雌激素对乳腺病变发展的影响；2)研究一旦病变发生，雌激素对肿瘤进展的影响；3)确定PRL、转化生长因子α和雌激素之间协同作用的途径，以促进体外和体内的癌变。总之，这些研究将阐明PRL、转化生长因子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目标。

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.