SnoN in regulating mammary gland development and tumorigenesis

SnoN 调节乳腺发育和肿瘤发生

• 批准号: 8756562
• 负责人: KUNXIN LUO
• 金额: $ 17.02万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8756562
• 关键词: Adult; Alveolar; Binding; Biochemical; Biological Models; Breast Cancer Cell; Breast Carcinogenesis; Breast Epithelial Cells; Clinical Treatment; Development; Ensure; Epithelial; Event; Genetic Transcription; Gland; Goals; Growth Factor; Human; In Vitro; Lactation; Maintenance; Malignant - descriptor; Mammary Neoplasms; Mammary gland; Modeling; Molecular; Molecular Profiling; Neoplasm Metastasis; Pathway interactions; Pharmaceutical Preparations; Play; Population; Pregnancy; Prolactin; Regulation; Role; STAT5A gene; Signal Transduction; Smad Proteins; Smad protein; Somatotropin; Staging; Stem cells; Testing; Time; design; in vivo; malignant breast neoplasm; mammary gland development; mouse model; new therapeutic target; novel therapeutics; outcome forecast; progenitor; programs; public health relevance; tumor progression; tumorigenesis

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.

描述（由申请人提供）：基础样的乳腺癌是人类乳腺癌最具侵略性的亚型，其恶性等级较高，转移性趋势增加和预后不良。当前的治疗选择极为有限，迫切需要新的靶向治疗。最近的进步表明，基础乳腺癌源自乳腺腔祖先种群，人类基底样乳腺肿瘤和腔祖细胞具有相似的分子特征。这项研究的目的是了解调节乳腺发光祖细胞命运的信号传导事件，以及这些调节计划的破坏如何有助于基础乳腺癌的进展，并强调TGF之间的串扰如何？ SNON协调了STAT5信号传导。乳腺管腔祖细胞源自乳腺干细胞，并负责成年腺体妊娠/哺乳期间的大规模上皮膨胀。关于控制该腔祖先命运的建立和维持的分子/途径，知之甚少。过去的研究表明，怀孕期间的上皮扩张受到包括TGF在内的生长因子和激素的调节？和催乳素。催乳素（通过STAT5发出信号传导）促进肺单术和泌尿作用，但TGF？通过SMADS功能抑制它们。 TGF的这种负面影响？必须在怀孕晚期抑制以确保适当的肺单术。 TGF怎么样？尚未定义信号传导在此临界点处与 /STAT5途径协调。 SNON是TGF的关键负面调节因子吗？通过与Smads结合并抑制其转录活性来传导。我们发现在乳腺中，妊娠晚期和早期泌乳时，SNON表达急剧上调。使用具有改变SNON表达的小鼠模型以及3D分化模型系统，我们已经确定了SNON在实现肺泡术和泌乳发作中的先前未识别的作用，这可能是通过促进STAT5的稳定性和激活来促进的。由于STAT5是建立腔祖细胞所必需的，因此我们假设SNON通过协调STAT5和TGF的活性来促进腔祖细胞命运来调节肺泡术。信号传导：通过增强STAT5表达和激活以及同时抑制SMAD信号传导。在基础乳腺癌细胞中，SNON和STAT5表达的异常调节可能促进肿瘤发生。已经设计了两个具体目标，以在体内和体外检验这一假设。目的，我将使用小鼠模型在体内确定SNON调节STAN调节和SMADS在体内乳腺肺单术和肿瘤发生的重要性。在AIM 2中，我们将确定SNON增强STAT5表达和激活的分子机制。我们的研究可能会确定腔内祖细胞命运和驱动基础乳腺癌进展的关键途径的重要决定因素。这可能有助于开发用于治疗基础乳腺癌的新型治疗药物。