Prolactin as a Growth Factor in Breast Cancer

催乳素作为乳腺癌的生长因子

• 批准号: 7002331
• 负责人: Nira Ben-Jonathan
• 金额: $ 36.71万
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002331
• 关键词: BCL2 gene /protein; adipose tissue; athymic mouse; autocrine; breast neoplasms; cell differentiation; gene expression; glycosylation; growth factor; hormone receptor; hormone regulation /control mechanism; human tissue; liposarcoma; molecular oncology; neoplastic growth; paracrine; prolactin; receptor expression

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，饮食和荷尔蒙因素的影响。催乳素（PRL）在啮齿动物中的乳腺肿瘤发生中的作用已被广泛接受，但其参与人类乳腺癌一直存在争议。 PRL是一种多效激素，是在不同调节机制下由垂体和非垂体部位产生的。最近的研究表明，PRL及其受体（PRL-R）在人乳房中的表达，但产生PRL的细胞类型，调节其表达以及局部PRL是否促进了体内乳腺癌的生长。 初步结果：我们发现Novo的合成和PRL表达的时间依赖性增加并从人类乳腺外植体中释放。脂肪中的PRL产生明显高于腺体或恶性组织。在乳腺前脂肪细胞分化期间，早期诱导了PRL表达，而其受体（PRLR）的表达逐渐增加，与Ieptin的升高平行。 PRL和PRL-R在两个人脂肪肉瘤细胞系中也表达。为了测试局部生产的PRL促进肿瘤生长的概念，将PRL转录本稳定转染到乳腺癌细胞中。过表达PRL的克隆的增长速度快于体外对照，并在裸鼠中形成更快的生长肿瘤。源自过表达PRL的克隆的肿瘤具有升高的PRL-R和抗凋亡剂Bcl-2的水平。我们的主要前提是乳腺脂肪组织是局部PRL的主要来源，它是促进肿瘤生长的细胞因子。为了进一步了解乳腺脂肪PRL，我们将首先确定PRL及其受体在乳腺脂肪组织和前脂肪细胞中的受体调节。然后，我们将用四环素诱导的PRL表达产生癌细胞，并分析旁分泌/自分泌PRL在体外和体内刺激肿瘤生长的机制。 假设：脂肪PRL的产生通常受到补品抑制作用抑制，但是肿瘤会产生克服这种抑制作用的PRL刺激因子。局部PRL的增加激活了刺激肿瘤生长的有丝分裂和抗凋亡信号。 特定的目标1将在乳腺脂肪组织中表征PRL及其受体。 \ \ 特定的目标2将定义乳腺癌细胞和脂肪肉瘤细胞中PRL表达的控制。 具体目标3将检查诱导型PRL表达对肿瘤生长和基因表达的影响。长期目标：将PRL建立为乳腺癌中的有丝分裂原/抗凋亡因素，是设计未来乳腺癌疗法的基础。