Role of StAR-related lipid transfer protein 10 in alcohol-induced breast cancer progression

StAR相关脂质转移蛋白10在酒精诱导的乳腺癌进展中的作用

• 批准号: 10734533
• 负责人: Maria Lauda Tomasi
• 金额: $ 44.95万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734533
• 关键词: Alcohol abuse; Alcohol consumption; Alcohols; Binding; Biological; Biological Process; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Cancer cell line; Breast Cancer therapy; Breast Feeding; CRISPR/Cas technology; Cell Nucleus; Cell Proliferation; Cell Survival; Cell membrane; Cells; Complex; DNA Damage; Data; Development; ERBB2 gene; Endoplasmic Reticulum; Epithelium; Estrogens; Ethanol; Exhibits; Family member; Gene Expression Regulation; Genes; Growth; Homeostasis; Hormones; Human; In Vitro; Invaded; Knowledge; Lecithin; Link; Lipids; Lysine; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Membrane; Membrane Fluidity; Mesenchymal; Modification; Mouse Mammary Tumor Virus; Mutate; Nuclear Import; Nuclear Translocation; Organoids; Pathway interactions; Patients; Peptide Mapping; Phosphatidylethanolamine; Phosphatidylinositol Phosphates; Phosphorylation; Play; Process; Prognosis; Proliferating; Protein Dephosphorylation; Protein Tyrosine Kinase; Protein phosphatase; Proteins; Proteomics; Public Health; Receptor Protein-Tyrosine Kinases; Recurrence; Regulation; Relapse; Reporting; Research; Risk; Role; Second Messenger Systems; Signal Transduction; Testing; Therapeutic; Threonine; Transgenic Mice; Transplantation; Tyrosine; Woman; Work; alcohol exposure; alcohol response; beta Karyopherins; breast cancer progression; cancer cell; casein kinase I; cell growth; cell motility; chronic alcohol ingestion; crosslink; experimental study; in vivo; lipid transfer protein; malignant breast neoplasm; migration; mouse model; new therapeutic target; novel; overexpression; p65; precise genome editing; prevent; receptor; receptor expression; receptor function; symporter; targeted treatment; therapeutic target; trafficking; transcription factor; tumorigenesis

ABSTRACT Several studies demonstrated that daily alcohol consumption (~1g) increases breast cancer risk by ~20% in women by promoting estrogen and other hormones, DNA damage as well as cell proliferation and epithelial– mesenchymal transition. Receptor tyrosine-protein kinase 2 (ErbB2) is a transmembrane receptor with intrinsic tyrosine kinase activity that plays an important role in human malignancies providing an enhanced response to ethanol-stimulated cell growth, invasion and migration. Normally, 20 ~ 30% of breast cancer with poor prognosis and relapse are ErbB2-positive. Alcohol appears to control signaling parameters of both upstream and downstream ErbB2 targets. Despite the efficacy of ErbB2-targeting therapy for breast cancer, only a fraction of patients responds successfully to therapy, while risks of recurrence are still high. The StAR related lipid transfer protein 10 (StarD10) is a phospho protein lipid transporter that shuttle the molecules from the endoplasmic reticulum through the plasma membrane and regulates its integrity, well-known to be altered during cell cancer transformation. StarD10 was described to be co-expressed with ErbB2 in 35% of primary human breast cancers, thereby supporting its role in deregulated cell growth and tumorigenesis. We recently reported that ethanol administration enhances StarD10 expression via ErbB2-induced p65 in MMTV-neu transgenic mice and in breast cancer cell lines. Also, StarD10 overexpression increases membrane fluidity, while ethanol promotes its dephosphorylation at tyrosine 288 residue (T288) points towards a lipid-related phenomenon. This proposal tests the novel hypothesis that ethanol induces changes in StarD10 biological activity, which may play a key role in breast cellular homeostasis thereby regulating malignancy/aggressiveness defining a novel therapeutic target. Aim 1: Examine how phosphorylation of StarD10 influences its biological function upon alcohol exposure in breast cancer. We will define the role of StarD10 phosphorylation (pStarD10) in ethanol-induced in breast cancer using CRISPR–Cas9 technology for the precise genome editing of pStarD10 at threonine 288 residue impacting on its lipid transporter activity, thus on plasma membrane fluidity. Aim 2: Examine the role of ethanol-induced StarD10 activity in ErbB2 signaling. We will investigate whether the phospho status of StarD10 influences ErbB2 activity and downstream pathways by its role as lipid transporter. Also, ErbB2 nuclear translocation will be examine. Aim 3: Examine the effects of StarD10 L260 gene editing in ethanol-fed breast cancer model. We will investigate whether protein phosphatase 2A (PP2A) activates StarD10 by dephosphorylating T288 residue inhibits aggressiveness in vitro ethanol-treated human breast cancer organoids (hBr-OUs) and in vivo hBr-OUs transplanted mouse model when the PP2A is mutated by CRISPR technology. Successful completion of these aims should enhance our knowledge of the complex interplay between the StarD10 phosphorylation and ErbB2 cell signaling ethanol-induced breast cancer, topics that are highly relevant to public health.

摘要 几项研究表明，每天饮酒（约1克）会使乳腺癌风险增加约20%。 女性通过促进雌激素和其他激素，DNA损伤以及细胞增殖和上皮细胞- 间质转化受体酪氨酸蛋白激酶2（ErbB2）是一种跨膜受体，具有内源性酪氨酸激酶活性。 酪氨酸激酶活性在人类恶性肿瘤中起重要作用， 乙醇刺激的细胞生长、侵袭和迁移。正常情况下，20~30%的乳腺癌预后不良 和复发者都是ErbB2阳性。酒精似乎控制上游和下游的信号参数。 下游ErbB2靶点。尽管ErbB2靶向治疗对乳腺癌有效，但只有一小部分人认为， 患者对治疗反应良好，但复发风险仍然很高。StAR相关的脂质转移 蛋白10（StarD10）是一种磷酸化蛋白脂质转运蛋白， 网通过质膜，并调节其完整性，众所周知，在细胞癌期间改变 转型StarD10被描述为在35%的原发性人类乳腺癌中与ErbB2共表达， 从而支持其在失调的细胞生长和肿瘤发生中的作用。我们最近报道了乙醇 在MMTV-neu转基因小鼠和乳腺癌中，通过ErbB 2诱导的p65， 癌细胞系。此外，StarD10过表达增加了膜流动性，而乙醇促进了其表达。 在酪氨酸288残基（T288）处的去磷酸化指向脂质相关现象。该提案测试 新的假设是，乙醇诱导StarD10生物活性的变化，这可能在 乳腺细胞稳态，从而调节恶性/侵袭性，定义了新的治疗靶点。 目的1：研究StarD10的磷酸化如何影响其对酒精的生物学功能 暴露在乳腺癌中我们将定义StarD10磷酸化（pStarD10）在乙醇诱导的细胞凋亡中的作用。 在乳腺癌中使用CRISPR-Cas9技术在苏氨酸288处对pStarD10进行精确基因组编辑 残基影响其脂质转运蛋白活性，从而影响质膜流动性。目标2：检查角色 乙醇诱导的StarD10在ErbB2信号传导中的活性。我们将调查是否磷酸化状态的 StarD10通过其作为脂质转运蛋白的作用影响ErbB2活性和下游途径。此外，ErbB2核 将检查易位。目的3：检查StarD10 L260基因编辑在乙醇喂养的乳房中的作用 癌症模型我们将研究蛋白磷酸酶2A（PP2A）是否通过以下途径激活StarD10： 去磷酸化T288残基抑制乙醇处理的人乳腺癌体外类器官的侵袭性 在PP2A通过CRISPR技术突变时的hBr-OU（hBr-OUs）和体内hBr-OUs移植小鼠模型中， 这些目标的成功实现应能增进我们对环境与发展之间复杂的相互作用的认识。 StarD10磷酸化和ErbB2细胞信号乙醇诱导的乳腺癌，高度相关的主题 公共卫生。