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: 7362396
• 负责人: LISA M ARENDT
• 金额: $ 11.83万
• 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/7362396
• 关键词: Adenocarcinoma; Advisory Committees; Attention; Biological; Biological Models; Breast; Breast Adenocarcinoma; Cell Line; Complex; Condition; Development; Diagnosis; Diagnostic; Disease; Disease model; 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; Invasive; 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; Protein Overexpression; 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; 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