Prolactin as a Growth Factor in Breast Cancer

催乳素作为乳腺癌的生长因子

• 批准号: 7339285
• 负责人: Nira Ben-Jonathan
• 金额: $ 23.87万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339285
• 关键词: Abbreviations; Adipose tissue; Affect; American Type Culture Collection; Apoptotic; Biochemical; Body mass index; Bos taurus; Breast; Breast Cancer Cell; Breast Carcinoma; Bromodeoxyuridine; CCAAT-Enhancer-Binding Proteins; Cattle; Cell Line; Cells; Charcoal; Conditioned Culture Media; Deoxyuridine; Estrogen Receptors; Foundations; Future; Gene Expression; Genes; Genetic; Goals; Growth; Growth Factor; Heparin Binding; Hormonal; Hormones; Human; IL2 gene; In Vitro; Insulin-Like Growth Factor I; Interleukin-2; Janus kinase 2; Leptin; Lymphocyte; Malignant - descriptor; Mammary Tumorigenesis; Mitogen-Activated Protein Kinase Kinases; Mitogens; Nucleotides; Nude Mice; PRLR gene; Peroxisome Proliferator-Activated Receptors; Personal Satisfaction; Pituitary Gland; Production; Prolactin; Prolactin Receptor; Property; Protein Overexpression; Rattus; Regulation; Rodent; Role; STAT protein; Serum; Signal Transduction; Site; Source; Testing; Tetanus Helper Peptide; Tetracycline; Tetracyclines; Time; Tissues; Transcript; Transcriptional Activation; Tumor-Derived; Untranslated Regions; autocrine; cancer cell; cancer therapy; cell type; concept; cytokine; design; fetal; glycosylation; in vivo; lipoprotein lipase; liposarcoma; malignant breast neoplasm; paracrine; receptor; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Breast cancer is affected by genetic, environmental, dietary and hormonal factors. The role of prolactin (PRL) in mammary tumorigenesis in rodents is well accepted but its involvement in human breast cancer has been controversial. PRL is a pleiotropic hormone that is produced by pituitary and non-pituitary sites under dissimilar regulatory mechanisms. Recent studies revealed expression of PRL and its receptor (PRL-R) in the human breast but the cell type that produces PRL, the regulation of its expression and whether local PRL promotes breast cancer growth in vivo have not been resolved. Preliminary Results: We found de-novo synthesis and time-dependent increases in PRL expression and release from human breast explants. PRL production was significantly higher in adipose than in glandular or malignant tissues. PRL expression was induced early during differentiation of breast preadipocytes whereas the expression of its receptor (PRLR) increased progressively, paralleling the rise in ieptin. Both PRL and the PRL-R were also expressed in two human liposarcoma cell lines. To test the concept that locally-produced PRL promotes tumor growth, the PRL transcript was stably transfected into breast cancer cells. Clones overexpressing PRL grew faster than controls in vitro and formed faster growing tumors in nude mice. Tumors derived from the PRL-overexpressing clones had increased levels of the PRL-R and the anti-apoptotic agent Bcl-2. Our main premise is that breast adipose tissue is the major source of local PRL which acts as a cytokine to promote tumor growth. To gain more understanding of breast adipose PRL, we will first determine the biochemical properties and regulation of PRL and its receptor in breast adipose tissue and preadipocytes. We will then generate cancer cells with a tetracycline-inducible PRL expression and analyze the mechanism by which paracrine/autocrine PRL stimulates tumor growth in vitro and in vivo. Hypothesis: Adipose PRL production is normally suppressed by tonic inhibition, but tumors produce PRL stimulatory factors that overcome this inhibition. The rise in local PRL activates mitogenic and anti-apoptotic signaling that stimulate tumor growth. Specific Aim 1 will characterize PRL and its receptor in breast adipose tissue. \ Specific Aim 2 will define the control of PRL expression in breast preadipocytes and liposarcoma cells. Specific Aim 3 will examine the effects of inducible PRL expression on tumor growth and gene expression. Long Term Goal: To establish PRL as a mitogen/anti-apoptotic factor in breast cancer, serving as the foundation for the design of future breast cancer therapy.

描述（由申请人提供）：乳腺癌受遗传、环境、饮食和激素因素的影响。催乳素（PRL）在啮齿动物乳腺肿瘤发生中的作用已被广泛接受，但其在人类乳腺癌中的作用一直存在争议。PRL是一种多效性激素，由垂体和非垂体部位在不同的调节机制下产生。近年来的研究发现，PRL及其受体（PRL- r）在人乳腺中有表达，但产生PRL的细胞类型、对其表达的调控以及局部PRL在体内是否促进乳腺癌的生长尚未明确。