SnoN in regulating mammary gland development and tumorigenesis

描述(申请人提供)：基底细胞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，转移倾向较高，预后较差。目前的治疗选择极其有限，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腔前体细胞群体，人类基底细胞样乳腺肿瘤和腔前体细胞具有相似的分子特征。本研究的目的是了解调控乳腺腔前体细胞命运的信号事件，以及这些调控程序的中断如何促进基础乳腺癌的进展，重点是如何在转化生长因子？STAT5信令由SnoN协调。乳腺腔祖细胞来源于乳腺干细胞，在妊娠/哺乳周期中负责成人腺体的大量上皮扩张。关于控制这一流明先祖命运的建立和维持的分子/途径，我们知之甚少。过去的研究表明，怀孕期间的上皮扩张受到生长因子和激素的调节，包括转化生长因子？还有催乳素。催乳素通过STAT5信号转导促进肺泡生成和乳汁生成，而转化生长因子？通过SMADs发挥作用，抑制它们。这种对转化生长因子的负面影响？必须在妊娠晚期抑制，以确保适当的肺泡形成。如何转化？在这一关键时刻，信号被抑制并与/STAT5通路协调还没有定义。SnoN是转化生长因子β的关键负性调节因子。通过与Smad结合并抑制其转录活性来发出信号。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。利用SnoN表达改变的小鼠模型和3D分化模型系统，我们已经确定了SnoN在促进肺泡形成和哺乳开始中的一个先前未知的作用，可能是通过促进Stat5的稳定和激活。由于STAT5是建立腔前体细胞所必需的，我们推测SnoN通过协调STAT5和转化生长因子的活性来促进腔前体细胞的命运，从而调控肺泡发育。信号传导：通过增强STAT5的表达和激活，同时抑制Smad信号传导。在乳腺癌细胞中，SnoN和STAT5表达的异常调节可能促进肿瘤的发生。已经设计了两个特定的目标来在体内和体外验证这一假说。目的利用小鼠模型，研究SnoN对STAT5和Smads的调控在体内乳腺腺泡形成和肿瘤发生中的作用。在目标2中，我们将确定SnoN促进STAT5表达和激活的分子机制。我们的研究可能确定管腔祖细胞命运的重要决定因素和驱动基础乳腺癌进展的关键途径。这可能有助于开发治疗基底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.