Genetic Regulatory Network in Mammary Tumorigenesis

描述(申请人提供)：本提案的主要目标是研究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，几个WNT信号分子与不同形式的癌症的发展有关。WNT信号已被证实在乳腺的正常发育和肿瘤转化中发挥重要作用。我们以前已经证明，Axin负性调节Wnt信号，这是妊娠晚期小叶-肺泡发育所必需的。高水平的Axin诱导乳腺上皮细胞发生凋亡。此外，导致Wnt信号通路结构性激活的Axin突变与许多不同形式的人类癌症有关，包括乳腺癌。因此，Wnt-Axin信号网络对健康和疾病中的乳腺发育至关重要。乳腺癌仍然是女性癌症死亡的主要原因。大量研究一再证实，生育史是乳腺癌的最大风险/保护因素。与未分娩的妇女相比，早孕使一生中患乳腺癌的风险降低了50%。早孕的保护作用为实现人类乳腺癌的防治提供了一种手术模式。然而，人们对怀孕和哺乳期乳腺的基本变化知之甚少。最近的一项研究表明，产次诱导的乳腺上皮祖细胞有助于未分娩和分娩的腺体细胞组成的差异。这个新发现的祖细胞群体显示了干细胞的特征，可能为研究与怀孕和哺乳相关的保护因子(S)提供洞察力。为了研究Wnt-Axin信号网络在乳腺发育和肿瘤发生中的作用，我们将阐明Axin突变诱导乳腺癌的机制。Axin对乳腺发育的抑制作用提示其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。我们最近开发了一种小鼠转基因系统，该系统可以理想地操纵成年乳腺干细胞中的基因活性。使用这一新的方法，我们将确定WNT-Axin信号网络在胎次诱导的乳腺上皮祖细胞中的作用，反映它们对乳腺癌的耐受性。

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.