Human Prolactin antagonist as a Chemopreventive Agent

描述(由申请人提供)： 最近，人催乳素(HPRL)在乳腺肿瘤上皮细胞中的自分泌/旁分泌增殖作用被证实参与了乳腺癌的发生。更重要的是，最近的证据表明，hPRL可能通过激活JAK2激酶而结构性地激活癌基因HER2/neu。虽然这种交叉激活所涉及的分子事件还不清楚，但人们认为HER2/neu的结构性磷酸化是导致HER2/neu阳性乳腺癌预后差和对抗HER2/neu单抗治疗的临床反应不满意的原因之一。这项为期两年的初步研究的目的是利用双转基因小鼠模型，确定hPRL与HER2/neu，更重要的是hPRL拮抗剂(G129R)与HER2/neu相互作用后，乳腺基因表达的变化。我们特别感兴趣的是验证G129R可以作为化学预防药物来预防或推迟HER2/neu引发的乳腺癌的假设，并为未来的研究识别参与这一过程的基因。我们的具体目标是(1)将雄性小鼠金属硫蛋白I启动子(MT)hPRL转基因小鼠(MT/hPRL)和MT/G129R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(MT/PRL+MMTV/neu和MT/G129R+MMTV/neu)，(2)监测双转基因小鼠的乳腺成瘤率，以确定hPRL在HER2/neu诱发乳腺肿瘤中的作用和G129R潜在的化学预防作用。(3)利用商品化的基因芯片检测双转基因小鼠乳腺组织中基因表达的变化，以确定hPRL、G129R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HER2/neu阳性乳腺癌，而且为进一步研究HER2/neu阳性乳腺癌的治疗靶点以及开发HER2/neu特异性肿瘤抑制物奠定了坚实的基础。

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.