Tumor progression and apoptosis in mouse mammary gland

描述(由申请人提供) 本项目涉及两个主要目标：1)发现与乳腺肿瘤进展有关的新途径，特别是与激素依赖性丧失有关的途径；2)确定在乳腺退化过程中启动触发乳腺细胞程序性死亡的级联反应的事件。了解是什么决定了肿瘤细胞对细胞增殖和死亡的调控缺乏反应是实验肿瘤学的主要目标。就乳腺细胞而言，增殖和分化的主要控制因素之一是妊娠相关激素的作用。确定新的基因和途径，使乳腺上皮细胞从这样的控制中释放出来，是抗击乳腺癌的一个基本问题。这一过程的一个特殊方面将集中在我们的研究中：在长时间休眠后恢复生长的肿瘤的快速和侵略性行为。虽然这是癌症患者治疗中的一个相关问题，但目前还没有太多的细胞或分子方法来解决这个问题。我们的研究将使用新的MMTV变种来进行，这种变种可以诱导妊娠依赖性肿瘤进展为激素非依赖性行为。利用反向PCR技术，MMTV序列将为我们提供一个分子标签，用于克隆宿主基因组区域，当这些区域发生改变时，有助于肿瘤的进展。有人提出，在正常细胞中触发细胞凋亡的刺激，在肿瘤组织--乳腺--中无效，乳腺恢复到处女状态的过程被称为乳房退化。这一过程发生在每个哺乳期之后，并涉及到乳腺肺泡上皮细胞通过细胞凋亡的一个非常重要的减少。在过去的几年里，在断奶后立即激活的乳腺分泌细胞中的信号通路受到了科学界的极大关注。然而，决定启动这一进程的非常早期的原因仍然未知。我们项目中描述的实验的目的是研究这些早期事件，以确定缺乏哺乳是如何导致乳腺细胞死亡的。这个问题将通过体内和体外实验来解决。此外，我们将重点确定肿瘤细胞是否在导致乳腺上皮细胞死亡的信号通路中发生变化，以及这是否与肿瘤进展有关。

DESCRIPTION (provided by applicant) The present project addresses two main goals: 1) Discovering new pathways involved in mammary tumor progression, particularly those related to the loss of hormone-dependency; and 2) determine the events that initiate the cascades that trigger programmed mammary cell death during mammary gland involution. Understanding what determines the neoplastic-cell lack of response to the regulatory controls for cell proliferation and death is the main goal for experimental oncology. In the case of mammary cells, one of the main controls for proliferation and differentiation resides in the action of pregnancy-related hormones. Determine new genes and pathways that release the mammary epithelial cells from such a control is a fundamental issue in the fight against breast cancer. A particular aspect of this process will be focused in our studies: the fast and aggressive behavior of tumors that resume growth after long periods of dormancy. Although a relevant issue in the treatment of cancer patients, there have not been too many cellular or molecular approaches to this issue. Our studies will be carried out using new MMTV variants that induce pregnancy-dependent tumors that progress to a hormone-independent behavior. Using the Inverse PCR technique, the MMTV sequences will provide us a molecular tag for cloning host genomic regions that, when altered, contribute to tumor progression. It has been proposed that stimuli that trigger apoptosis in normal ceils, would fail in neoplastic tissue, the mammary gland, the process by which the lactating gland goes back to a virgin-like state is known as mammary involution. This process takes place after each lactation period and involves a very important reduction, by apoptosis, of the mammary alveolar epithelium. The signaling pathways that become activated in the mammary secretory cells right after weaning have received a lot of attention in the scientific community during the last years. However, the very early causes that determine the initiation of this process remain unknown. The purpose of the experiments described in our project is to study these early events to determine how the lack of suckling induces mammary cell death. This issue will be approached by in rive as well as in vitro experiments. In addition, we will focus in determining whether neoplastic cells show alteration in the signaling pathways that lead to mammary epithelium cell death and whether that would be relevant during tumor progression.