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: 7588885
• 负责人: LISA M ARENDT
• 金额: $ 12.12万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588885
• 关键词: Adenocarcinoma; Advisory Committees; Attention; Biological; Biological Models; Breast; Breast Adenocarcinoma; Cell Line; Complex; Development; Diagnosis; Diagnostic; Disease; Disease model; ERBB2 gene; Environment; Epidermal Growth Factor Receptor; Estrogen Receptor alpha; Estrogens; Female; Gene Expression Profiling; Gland; Growth; Growth and Development function; Heterodimerization; Hormonal; Human; Human Pathology; In Vitro; Knowledge; Lactation; Lead; Lesion; Mammary Neoplasms; Mammary gland; Mentors; Modeling; Mus; Normal tissue morphology; Oncogenes; Ovarian; Ovariectomy; PRLR gene; Pathogenesis; Pathway interactions; Principal Investigator; Process; Production; Program Development; Prolactin; Role; Science; Scientist; Signal Pathway; Signal Transduction; Supplementation; Testing; Training Programs; Transforming Growth Factor alpha; Transgenic Mice; Transgenic Model; Tumor Tissue; United States; Woman; carcinogenesis; career; human disease; improved; in vivo; in vivo Model; insight; interest; malignant breast neoplasm; outcome forecast; overexpression; programs; promoter; receptor; research study; response; skills; therapeutic target; tool; tumor; tumor progression

This proposal describes a 5 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 lab 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, TGFa, and estrogen that may enhance carcinogenesis in vitro and in vivo. Together these studies will illuminate the cooperative roles of PRL, TGFa, and estrogen in the progression of breast cancer and could lead to useful diagnostic strategies and improved theraputic targets.

该提案描述了一个为期5年的培训计划，以发展学术生涯， 生物医学科学该计划将提高利用体内模型作为工具的关键技能， 理解复杂的人类病理学琳达舒勒博士，催乳素领域公认的领导者 信号，将指导首席研究员的科学发展。一个高度- 著名科学家将为这个项目提供指导以及职业建议。 据估计，今年美国将有211，000名妇女被诊断患有浸润性乳腺癌。 年虽然开发治疗的重点是针对激素信号通路，但一个关键的差距是， 存在于关键因素之间的信号串扰的知识，这些因素共同导致生长失调， 这种疾病。催乳素（PRL）在乳腺发育、泌乳和退化中的核心作用， 在乳腺癌中的信号传导。舒勒实验室已经培育出了转基因小鼠， 在乳腺选择性非乳腺应答启动子NRL的控制下的PRL。这些老鼠 乳腺腺癌是雌激素受体α阳性和阴性的，与人类相似， 疾病鉴于雌激素及其受体在发病机制和治疗中的重要性， 该模型是研究疾病中PRL和雌激素之间相互作用的极好工具 发展和进步。另一个特征明确的乳腺癌基因，转化生长因子 TGF α与人类雌激素受体α阴性乳腺肿瘤相关， 在我们的转基因模型系统中与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癌的协同作用的假设， 催乳素和TGF α促进肿瘤发展和进展。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）调查 一旦病变发展，雌激素对肿瘤进展的影响，以及3）鉴定 PRL、TGF α和雌激素之间的协同串扰途径可能会增强肿瘤的发生， 体外和体内。总之，这些研究将阐明PRL、TGF α和雌激素在乳腺癌中的协同作用。 乳腺癌的进展，并可能导致有用的诊断策略和改善治疗 目标的