Prolactin as a Growth Factor in Breast Cancer

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）在啮齿类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。最近的研究揭示了PRL及其受体（PRL-R）在人类乳腺中的表达，但是产生PRL的细胞类型、其表达的调节以及局部PRL是否促进体内乳腺癌生长尚未解决。 初步结果：我们发现从人乳腺外植体中PRL表达和释放的从头合成和时间依赖性增加。PRL的产生显着高于脂肪比腺体或恶性组织。催乳素的表达诱导早期乳腺前脂肪细胞的分化过程中，而其受体（PRLR）的表达逐渐增加，平行于在ieptin的上升。PRL和PRL-R也在两个人脂肪肉瘤细胞系中表达。为了测试局部产生的PRL促进肿瘤生长的概念，将PRL转录物稳定转染到乳腺癌细胞中。过表达PRL的克隆在体外比对照生长得更快，在裸鼠中形成更快生长的肿瘤。来自PRL过表达克隆的肿瘤具有增加的PRL-R和抗凋亡剂Bcl-2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，PRL作为细胞因子促进肿瘤生长。为了更好地了解乳腺脂肪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生化特性和调控。然后，我们将产生具有四环素诱导的PRL表达的癌细胞，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的产生通常受到紧张性抑制的抑制，但肿瘤产生PRL刺激因子，克服这种抑制。局部PRL的升高激活了刺激肿瘤生长的促有丝分裂和抗凋亡信号。 特异性目的1将表征乳腺脂肪组织中的PRL及其受体。\ 具体目标2将定义乳腺前脂肪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：建立PRL作为乳腺癌中的促分裂/抗凋亡因子，作为未来乳腺癌治疗设计的基础。

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.