Genetic Regulatory Network in Mammary Tumorigenesis

描述（由申请人提供）：本提案的主要目的是研究Wnt-Axin信号网络调节乳腺发育和乳腺癌的机制。Wnt信号控制关键的发育过程，并且几种Wnt信号传导分子已经涉及不同形式的癌症的发展。Wnt信号转导在乳腺的正常发育和肿瘤转化中起着重要作用。我们以前已经证明，Axin负调节Wnt信号，这是所需的小叶肺泡发育在妊娠晚期。高水平的Axin诱导乳腺上皮细胞发生凋亡。此外，导致Wnt信号通路组成性激活的Axin突变与许多不同形式的人类癌症（包括乳腺癌）有关。因此，Wnt-Axin信号网络对于健康和疾病中的乳腺发育至关重要。乳腺癌仍然是妇女癌症死亡的主要原因。许多研究一再证实，生育史是乳腺癌最强的风险/保护因素。与未经生育的妇女相比，早期怀孕使乳腺癌的终生风险降低50%。早期妊娠的保护作用为实现人类乳腺癌的预防和治疗提供了一个可操作的模型。然而，很少有人知道的基本变化的乳腺在怀孕和哺乳期。最近的一项研究表明，产次诱导的乳腺上皮祖细胞有助于在未经产和经产腺体之间的细胞组成的差异。这种新发现的祖细胞群显示出干细胞的特征，可能有助于了解与妊娠和哺乳相关的保护因素。为了研究Wnt-Axin信号网络在乳腺发育和肿瘤发生中的参与，我们将阐明Axin突变体诱导乳腺癌的机制。Axin对乳腺发育的抑制作用提示Axin可能干扰了致癌信号通路诱导的恶性转化。我们将探讨Axin肿瘤抑制因子在乳腺肿瘤发生中的作用。我们最近开发了一个小鼠转基因系统，这是理想的操纵基因活性，特别是在成年乳腺干细胞。使用这种新方法，我们将确定Wnt-Axin信号网络在产次诱导的乳腺上皮祖细胞中的作用，反映其对乳腺癌的难治性。

DESCRIPTION (provided by applicant): The primary objective of this proposal is to investigate the mechanisms by which the Wnt-Axin signaling network regulates mammary gland development and breast cancer. Wnt signals control key developmental processes and several Wnt signaling molecules have been implicated in the development of different forms of cancer. Wnt signaling has been well established to play an important role in normal development as well as neoplastic transformation of the mammary gland. We have demonstrated previously that Axin negatively modulates a Wnt signal that is required for lobulo-alveolar development in late pregnancy. High levels of Axin induce mammary epithelia to undergo apoptosis. In addition, mutations of Axin that lead to constitutive activation of the Wnt signaling pathway have been linked to many different forms of human cancers, including breast cancer. Therefore, the Wnt-Axin signaling network is critical for mammary gland development in health and disease. Breast cancers remain the major leading cause of cancer mortality in women. Numerous studies have repeatedly confirmed that reproductive history represents the strongest risk/protective factor for breast cancer. Pregnancy at an early age confers a 50% reduction in lifetime risk of breast cancer as compared with nulliparous women. The protective effect of early pregnancy provides an operative model to achieve breast cancer prevention and therapy in humans. However, very little is known about fundamental changes of the mammary gland during pregnancy and lactation. A recent study showed that the parity-induced mammary epithelial progenitors contribute to differences in cellular composition between the nulliparous and parous glands. This newly identified progenitor population, displaying stem cell characteristics, may provide insight toward the protective factor(s) associated with pregnancy and lactation. To investigate the involvement of the Wnt-Axin signaling network in mammary gland development and tumorigenesis, we will elucidate the mechanisms by which the Axin mutant induces breast cancer. The inhibitory effect of Axin on mammary gland development suggests that it might interfere with malignant transformation induced by oncogenic signaling pathways. We will explore the role of the Axin tumor suppressor in mammary tumorigenesis. We have recently developed a mouse transgenic system, which is ideal to manipulate gene activity specifically in the adult mammary stem cell. Using this novel approach, we will determine the role of the Wnt-Axin signaling network in the parity-induced mammary epithelial progenitors, reflecting their refractoriness to breast cancer.