SnoN in regulating mammary gland development and tumorigenesis

描述（申请人提供）：基底样乳腺癌是人类乳腺癌中最具侵袭性的亚型，恶性程度较高，转移倾向增加，预后差。目前的治疗方案极其有限，迫切需要新的靶向治疗。最近的研究表明，基底乳腺癌起源于乳腺管腔祖细胞群，人类基底样乳腺肿瘤和管腔祖细胞具有相似的分子特征。本研究的目的是了解调节乳腺腔祖细胞命运的信号事件，以及这些调节程序的破坏如何促进基础乳腺癌的进展，重点研究TGF？STAT5信号由SnoN协调。乳腺管状祖细胞来源于乳腺干细胞，在妊娠/哺乳周期中负责成体腺体上皮细胞的大量扩增。对于控制这种腔内祖细胞命运的建立和维持的分子/途径知之甚少。过去的研究表明，妊娠期间上皮细胞的扩张受生长因子和激素的调节，包括TGF？和催乳激素。而催乳素通过STAT5信号传导，促进肺泡生成和乳生成，TGF？通过smad发挥作用，抑制它们。TGF？在妊娠后期必须抑制，以确保适当的肺泡形成。TGF如何?在这个关键时刻，信号被抑制并与/STAT5通路协调尚不明确。SnoN是TGF?的关键负调控因子通过与smad结合并抑制其转录活性来传递信号。我们发现，在乳腺中，SnoN的表达在妊娠晚期和哺乳期早期急剧上调。通过使用SnoN表达改变的小鼠模型以及3D分化模型系统，我们发现了SnoN在促进肺泡形成和泌乳发生中的作用，可能是通过促进Stat5的稳定性和激活。由于Stat5是建立腔内祖细胞所必需的，我们假设SnoN通过协调Stat5和TGF？信号传导：通过增强STAT5的表达和激活，同时抑制Smad信号传导。在基底乳腺癌细胞中，SnoN和STAT5表达的异常调控可能促进肿瘤的发生。为了在体内和体外验证这一假设，已经设计了两个特定的目标。目的通过小鼠模型，确定SnoN调控STAT5和Smads在乳腺肺泡形成和肿瘤发生中的重要性。在目的2中，我们将确定SnoN增强STAT5表达和激活的分子机制。我们的研究可能确定腔内祖细胞命运的重要决定因素和驱动基底乳腺癌进展的关键途径。这可能有助于开发治疗基底性乳腺癌的新型治疗药物。

DESCRIPTION (provided by applicant): Basal-like breast cancer is the most aggressive subtype of human breast cancer with a higher malignant grade, increased metastatic tendency and poor prognosis. Current treatment options are extremely limited, and new targeted therapy is urgently needed. Recent advances suggest that basal breast cancer originate from the mammary luminal progenitor population, and human basal-like breast tumors and luminal progenitor cells share a similar molecular signature. The objective of this study is to understand the signaling events that regulate mammary luminal progenitor cell fate and how disruption of these regulatory program contributes to basal breast cancer progression, with an emphasis on how the crosstalk between TGF? and STAT5 signaling is coordinated by SnoN. The mammary luminal progenitor cells are derived from the mammary stem cells and are responsible for the massive epithelial expansion during the pregnancy/lactation cycles in the adult glands. Little is known about the molecules/pathways that control the establishment and maintenance of this luminal progenitor fate. Past studies have shown that epithelial expansion during pregnancy is regulated by growth factors and hormones, including TGF? and prolactin. While prolactin, signaling through STAT5, promotes alveologenesis and lactogenesis, TGF? functioning via the Smads, inhibits them. This negative effect of TGF? must be suppressed during late pregnancy to ensure proper alveologenesis. How TGF? signaling is suppressed and coordinated with /STAT5 pathway at this critical juncture has not been defined. SnoN is a critical negative regulator of TGF? signaling by binding to the Smads and repressing their transcription activity. We found that in the mammary gland, SnoN expression is sharply upregulated at late pregnancy and early lactation. Using mouse models with altered expression of SnoN as well as a 3D differentiation model system, we have identified a previously unrecognized role of SnoN in enabling alveologenesis and onset of lactation, likely through promoting Stat5 stability and activation. Since Stat5 is required for the establishment of luminal progenitor cells, we hypothesize that SnoN regulates alveologenesis by promoting luminal progenitor cell fate through co-ordinating the activities of STAT5 and TGF? signaling: by enhancing STAT5 expression and activation and at the same time suppressing Smad signaling. In basal breast cancer cells, aberrant regulation of SnoN and STAT5 expression may promote tumorigenesis. Two specific aims have been designed to test this hypothesis in vivo and in vitro. Aim I will determine the importance of SnoN regulation of STAT5 and Smads in mammary alveologenesis and tumorigenesis in vivo using mouse models. In aim 2, we will determine the molecular mechanism by which SnoN enhances STAT5 expression and activation. Our study may identify important determinant of luminal progenitor cell fate and key pathways that drive basal breast cancer progression. This may facilitate development of novel therapeutic drugs for the treatment of basal breast cancer.