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（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。最近的进展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导致基底乳腺癌进展，重点是 TGF? STAT5 信号传导由 SnoN 协调。乳腺腔祖细胞源自乳腺干细胞，负责成体腺体妊娠/哺乳周期期间的大量上皮扩张。关于控制这种管腔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，怀孕期间的上皮扩张受到生长因子和激素的调节，包括TGF？和催乳素。催乳素通过 STAT5 发出信号，促进肺泡生成和乳汁生成，而 TGF？通过 Smads 发挥作用，抑制它们。 TGF的这种负面影响？必须在妊娠后期抑制，以确保适当的肺泡生成。转化生长因子如何？在此关键时刻，信号传导被抑制并与 /STAT5 通路协调尚未明确。 SnoN 是 TGF 的关键负调节因子？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 表达在妊娠晚期和哺乳早期急剧上调。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 在促进肺泡生成和泌乳开始方面以前未被认识到的作用，可能是通过促进 Stat5 稳定性和激活。由于 Stat5 是管腔祖细胞建立所必需的，因此我们假设 SnoN 通过协调 STAT5 和 TGF? 的活性来促进管腔祖细胞命运，从而调节肺泡生成？信号传导：通过增强 STAT5 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 表达的异常调节可能促进肿瘤发生。设计了两个具体目标来在体内和体外检验这一假设。目标我将使用小鼠模型确定 SnoN 调节 STAT5 和 Smads 在体内乳腺泡发生和肿瘤发生中的重要性。在目标 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管腔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乳腺癌的新型治疗药物。