PROGESTERONE RECEPTOR IN BREAST DEVELOPMENT AND CANCER

孕酮受体在乳房发育和癌症中的作用

• 批准号: 6965687
• 负责人: JOHN P LYDON
• 金额: $ 31.88万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965687
• 关键词: RNase protection assay; apoptosis; biological signal transduction; breast neoplasms; carcinogenesis; cell proliferation; cyclins; epidermal growth factor; gene targeting; genetically modified animals; genotype; green fluorescent proteins; histogenesis; histopathology; hormone related neoplasm /cancer; immunocytochemistry; laboratory mouse; mammary epithelium; mammary gland; phenotype; progesterone receptors

DESCRIPTION (provided by applicant): Considering the importance of the progesterone (P)-proliferative signal to mammary development and tumorigenesis, our long-term goal is to exploit experimental mouse genetics to gain a more mechanistic understanding of P's role as an endocrine mammogen, in vivo. Toward this end, our recent studies revealed that in the proliferating murine mammary gland, the majority of PR positive (+) cells were surprisingly nonproliferative but were in close association with a subgroup of PR negative (-) cells which proliferate in response to P; a similar cellular organization pattern for PR expression occurs in the human and rat mammary gland. Importantly, derailment of this distinct patterning for mammary PR expression is linked to a number of aberrant mammary growth phenotypes, including neoplasia. The foregoing observations strongly support our hypothesis of an evolutionary conserved cellular mechanism for P-action in the normal gland in which PR+ cells receive, transduce, and then relay (via a paracrine pathway) the P-proliferative signal to neighboring PR- cells, which are then directed toward a pathway of proliferation. Our hypothesis predicts the existence of an intraepithelial paracrine molecular pathway(s), which mediates the P-proliferative signal; the Wnt-4 pathway has been implicated as such a pathway. To test our hypothesis, Specific Aim 1 will employ our PR-LacZ reporter mouse, a recently generated PR-enhanced green fluorescent protein knockin mouse, fluorescence-activated cell sorting, and mammary epithelial transplantation approaches to query-at the cellular level-the functional importance of P's proposed paracrine mechanism of action in the normal mammary gland. Specific Aim 2 will define the developmental importance of PR expression during early mammary development to PR's function in the adult gland by using the tetracycline regulated expression system (the TET-ON system) to temporally control PR expression in the mammary epithelium of the PR knockout (PRKO) mouse. Using the TET-ON system and the PRKO, Specific Aim 3 will address whether Wnt-4 is a bona-fide paracrine mediator of the P-proliferative signal in the murine mammary gland. Finally, Specific Aim 4 will employ comparative transcriptional profiling of normal and PRKO mammary glands to identify the complete spectrum of paracrine mediators of the P-mammary signal. Application of microarray approaches to murine mammary tumor models (developed during the last grant period) will also uncover signature gene-networks specific for either hormone-dependent or -independent breast tumors; this aim should also furnish important molecular targets for future breast cancer diagnosis, prognosis and/or therapy.

描述（由申请人提供）：考虑到孕酮（P）-增殖信号对乳腺发育和肿瘤发生的重要性，我们的长期目标是利用实验小鼠遗传学来获得对P作为体内内分泌乳腺激素的作用的更机械的理解。为此，我们最近的研究表明，在增殖的小鼠乳腺中，大多数PR阳性（+）细胞令人惊讶的是非增殖性的，但与一个亚组的PR阴性（-）细胞，增殖响应P密切相关; PR表达的细胞组织模式相似，发生在人类和大鼠乳腺。重要的是，乳腺PR表达的这种独特模式的脱轨与许多异常的乳腺生长表型有关，包括肿瘤形成。上述观察结果强烈支持我们的假设，即在正常腺体中P-作用的进化保守的细胞机制，其中PR+细胞接收、传递，然后（通过旁分泌途径）将P-增殖信号传递给相邻的PR-细胞，然后将其导向增殖途径。我们的假设预测存在上皮内旁分泌分子通路，其介导P-增殖信号; Wnt-4通路被认为是这样的通路。为了验证我们的假设，具体目标1将采用我们的PR-LacZ报告小鼠，最近产生的PR增强的绿色荧光蛋白敲入小鼠，荧光激活细胞分选，和乳腺上皮移植的方法来查询-在细胞水平上的功能的重要性P的建议旁分泌作用机制在正常乳腺。具体目标2将通过使用四环素调节的表达系统（TET-ON系统）暂时控制PR敲除（PRKO）小鼠乳腺上皮中的PR表达，定义早期乳腺发育期间PR表达对PR在成年腺体中的功能的发育重要性。使用TET-ON系统和PRKO，特异性目标3将解决Wnt-4是否是鼠乳腺中P-增殖信号的真正旁分泌介体。最后，具体目标4将采用正常和PRKO乳腺的比较转录谱来鉴定P-乳腺信号的旁分泌介质的完整谱。微阵列方法应用于小鼠乳腺肿瘤模型（在最后一次资助期间开发）也将揭示对乳腺癌依赖性或非依赖性乳腺肿瘤特异性的特征基因网络;这一目标也将为未来的乳腺癌诊断、预后和/或治疗提供重要的分子靶点。