Human Prolactin antagonist as a Chemopreventive Agent

描述（由申请人提供）： 人催乳素（hPRL）在乳腺癌中的参与最近已经建立了基于其在乳腺肿瘤上皮细胞中的自分泌/旁分泌增殖作用。更重要的是，最近的证据表明，hPRL可能通过激活JAK 2激酶组成性激活癌基因HER 2/neu。尽管参与这种交叉激活的分子事件尚未完全了解，但据信HER 2/neu的组成性磷酸化导致HER 2/neu阳性乳腺癌对抗HER 2/neu单克隆抗体治疗的不良预后和不满意的临床应答。这项为期两年的初步研究的目的是使用双转基因小鼠模型，鉴定hPRL和HER 2/neu之间的相互作用，更重要的是hPRL拮抗剂（G129 R）和HER 2/neu之间的相互作用导致的乳腺中基因表达的改变。我们特别感兴趣的是测试G129 R可用作化学预防剂以预防或延迟HER 2/neu引发的乳腺癌的发病的假设，并鉴定参与该过程的那些基因以用于未来的研究。本研究的具体目标是：（1）通过雄性小鼠金属硫蛋白I启动子（MT）hPRL转基因小鼠（MT/hPRL）和MT/G129 R转基因小鼠与雌性MMTV/neu转基因小鼠杂交，建立双转基因小鼠品系（MT/PRL+MMTV/neu和MT/G129R+MMTV/neu），（2）监测双转基因小鼠乳腺肿瘤形成率，以确定hPRL在HER 2/neu诱导的乳腺肿瘤中的作用以及G129 R的潜在化学预防作用的功效，（3）利用商用cDNA微阵列技术检测双转基因小鼠乳腺组织中基因表达的改变，以确定hPRL、G129 R和HER/neu相互作用的基因组特征。我们希望这项初步研究的结果不仅有助于更好地了解HER 2/neu阳性乳腺癌，而且为进一步研究确定HER 2/neu阳性乳腺癌的治疗靶点以及开发HER 2/neu特异性肿瘤抑制剂奠定坚实的基础。

DESCRIPTION (provided by applicant): The involvement of human prolactin (hPRL) in breast cancer has been recently established based upon its autocrine/paracrine proliferative effects in mammary tumor epithelial cells. More importantly, recent evidence suggests that hPRL may constitutively activate oncogene HER2/neu through activation of JAK2 kinase. Although the molecular events involved in this cross activation is not well understood, it is believed that constitutive phosphorylation of HER2/neu contributes to poor prognosis and unsatisfactory clinical response of HER2/neu positive breast cancer to anti-HER2/neu monoclonal antibody therapy. The purpose of this two-year pilot study is to identify the alteration of gene expression in the mammary gland resulted from the interaction between hPRL and HER2/neu, more importantly between a hPRL antagonist (G129R) and HER2/neu, using bi-transgenic mouse models. We are especially interested to test the hypothesis that G129R can be used as a chemopreventive agent to prevent or delay the onset of HER2/neu initiated breast cancer and identify those genes involved in this process for future studies. Our specific aims are (1) to establish bi-transgenic mice by cross-breeding male mouse metallothionein I promoter (MT) hPRL transgenic mice (MT/hPRL) and MT/G129R transgenic mice with female MMTV/neu transgenic mouse to generate bi-transgenic lines (MT/PRL+MMTV/neu and MT/G129R+MMTV/neu), (2) to monitor the rate of breast tumor formation in bi-transgenic mice to determine the role of hPRL in HER2/neu induced breast tumor and the efficacy of potential chemopreventive effects of G129R, (3) to use commercial cDNA microaray services to identify alterations in gene expression in the mammary tissue of the bi-transgenic mice to identify genomic signatures of hPRL, G129R and HER/neu interaction. We hope that the results from this pilot study will not only contribute to a better understanding of the HER2/neu positive breast cancer but also lay a solid foundation for further studies to define therapeutic targets for HER2/neu positive breast cancer as well as to develop HER2/neu specific tumor inhibitors.