14-3-3zeta in Early Stages of Breast Cancer Progression

乳腺癌进展早期阶段的 14-3-3zeta

• 批准号: 7468439
• 负责人: Dihua Yu
• 金额: $ 26.42万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-09 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468439
• 关键词: 14-3-3 Family; Acinus organ component; Apoptosis; Axillary lymph node group; Basement membrane; Breast; Breast Cancer Treatment; CDKN1A gene; Cell Communication; Cell Polarity; Cell Proliferation; Cell model; Cell physiology; Cells; Clinical; Condition; Development; Diagnostic; Early Diagnosis; Epithelial; Epithelial Cells; Evolution; Gene Transfer; Growth; Immunohistochemistry; In Situ Nick-End Labeling; Integrins; Intervention; Intraductal Hyperplasia; Invasive; Lead; Localized; Mammary Neoplasms; Mammary gland; Modeling; Molecular; Negative Axillary Lymph Node; Neoplasm Metastasis; Non-Malignant; Noninfiltrating Intraductal Carcinoma; PCNA gene; Pathway interactions; Patients; Play; Property; Protein Overexpression; Proteins; Recurrence; Role; S-1 Antimetabolite agent; Signal Pathway; Simulate; Small Interfering RNA; Staging; Structure; Tissue Model; Tissues; Virus; base; caspase-3; in vivo; laminin-5; malignant breast neoplasm; member; mortality; mutant; novel; oncoprotein p21; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): Recent progress in diagnostic tools allows more breast cancers being detected at early pre-invasive stage. This brings imposing demands on better understanding of early stage breast cancer progression and how it may develop into invasive and metastatic breast cancers. Recently, we discovered that 14-3-3zeta, a member of the 14-3-3 family proteins that are highly conserved through evolution and participate in many important cellular processes, is overexpressed in >45% of breast cancers and this overexpression predicts poor patient survival. The increased expression of 14-3-3zeta begins at the stage of atypical ductal hyperplasia (ADH), a relatively early stage in the progression towards breast cancer, and can be detected in about 56% ductal carcinoma in situ (DCIS). We have investigated the impact of high-expressing 14-3-3zeta on normal mammary epithelial cells (MECs) in a three-dimensional (3D) culture model that simulates in vivo conditions of acini formation in the mammary gland and has retained MEC interactions with basement membrane (BM). We found that in contrast to the normal acini structures of control virus-infected MCF10A MECs, increasing 14-3-3zeta expression by retroviral gene transfer in MCF10A led to disorganized acini structures that showed loss of polarity, increased proliferation, and filling of the luminal space which is a hallmark of early breast cancers, such as ADH and DCIS. Based on these novel findings, we hypothesize that 14-3-3zeta is involved in the early stages of transformation of normal MECs and plays important roles in the early progression towards breast cancer. In this proposal, we will use the 3D culture model to determine the role of high-expressing 14-3-3zeta in the early transformations of MECs by investigating whether increasing 14-3-3zeta in nonmalignant MECs or blocking 14-3-3zeta in transformed MECs will alter acini structures and key properties involved in acini formation, including MEC polarity, apoptosis, and proliferative suppression (Aim 1). Then, we will further dissect the molecular mechanisms/signaling pathways by which high-expressing 14-3-3zeta disrupts acini structures and induces early transformation of MECs (Aim 2). Finally, we will confirm the importance of 14-3-3zeta in breast cancer progression in tissues from patients with untreated early stage node-negative breast tumors (Aim 3). These comprehensive approaches will define the role of 14-3-3zeta in early stage breast cancer progression, which could impact the early detection, intervention, and treatment of breast cancer. This effort will ultimately lead to a decrease in breast cancer metastasis and mortality.

描述（由申请人提供）：诊断工具的最新进展允许在早期侵入前发现更多的乳腺癌。 这使人们对早期乳腺癌进展以及如何发展为侵入性和转移性乳腺癌的需求征收了要求。 最近，我们发现14-3-3zeta是14-3-3家族蛋白的成员，通过进化高度保守并参与许多重要的细胞过程，在> 45％的乳腺癌中过表达，这种过表达预测患者的生存率差。 14-3-3ZETA的表达增加始于非典型导管增生阶段（ADH），这是朝着乳腺癌进展的相对早期阶段，可以在约56％的导管癌（DCIS）中检测到。 我们已经在三维（3D）培养模型中研究了高表达14-3-3zeta对正常乳腺上皮细胞（MEC）的影响，该模型模拟了乳腺中acini形成的体内条件，并保留了MEC与MEC与基层膜（BM）的影响。 我们发现，与对照病毒感染的MCF10A MEC的正常ACINI结构相反，在MCF10A中通过逆转录病毒基因转移增加了14-3-3zeta的表达，导致杂有组织的ACINI结构，这些结构显示出极性丧失，增加了增殖，增加了诸如早期乳腺癌的Hallmark，例如早期的乳腺癌，例如早期的乳腺癌。 基于这些新的发现，我们假设14-3-3zeta参与了正常MEC转化的早期阶段，并在早期进展中对乳腺癌起着重要作用。 In this proposal, we will use the 3D culture model to determine the role of high-expressing 14-3-3zeta in the early transformations of MECs by investigating whether increasing 14-3-3zeta in nonmalignant MECs or blocking 14-3-3zeta in transformed MECs will alter acini structures and key properties involved in acini formation, including MEC polarity, apoptosis, and proliferative suppression （目标1）。 然后，我们将进一步剖析高表达14-3-3zeta的分子机制/信号通路，破坏了ACINI结构并诱导MEC的早期转化（AIM 2）。 最后，我们将确认未经治疗的早期淋巴结阴性乳腺肿瘤患者的组织中14-3-3zeta在乳腺癌进展中的重要性（AIM 3）。 这些全面的方法将定义14-3-3zeta在早期乳腺癌进展中的作用，这可能会影响乳腺癌的早期发现，干预和治疗。 这项工作最终将导致乳腺癌转移和死亡率降低。

项目成果

Upregulation of neutrophil gelatinase-associated lipocalin by ErbB2 through nuclear factor-kappaB activation.

• DOI: 10.1158/0008-5472.can-09-2483
• 发表时间: 2009-12-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Li SH;Hawthorne VS;Neal CL;Sanghera S;Xu J;Yang J;Guo H;Steeg PS;Yu D
• 通讯作者: Yu D

Breast cancer metastasis: challenges and opportunities.

• DOI: 10.1158/0008-5472.can-09-0099
• 发表时间: 2009-06-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Lu, Jing;Steeg, Patricia S;Yu, Dihua
• 通讯作者: Yu, Dihua

Mitotic deregulation by survivin in ErbB2-overexpressing breast cancer cells contributes to Taxol resistance.

• DOI: 10.1158/1078-0432.ccr-08-0954
• 发表时间: 2009-02-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Lu J;Tan M;Huang WC;Li P;Guo H;Tseng LM;Su XH;Yang WT;Treekitkarnmongkol W;Andreeff M;Symmans F;Yu D
• 通讯作者: Yu D

ErbB2-mediated Src and signal transducer and activator of transcription 3 activation leads to transcriptional up-regulation of p21Cip1 and chemoresistance in breast cancer cells.

• DOI: 10.1158/1541-7786.mcr-08-0316
• 发表时间: 2009-04
• 期刊: Molecular cancer research : MCR
• 作者: Hawthorne VS;Huang WC;Neal CL;Tseng LM;Hung MC;Yu D
• 通讯作者: Yu D

14-3-3zeta overexpression defines high risk for breast cancer recurrence and promotes cancer cell survival.

• DOI: 10.1158/0008-5472.can-08-2765
• 发表时间: 2009-04-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Neal CL;Yao J;Yang W;Zhou X;Nguyen NT;Lu J;Danes CG;Guo H;Lan KH;Ensor J;Hittelman W;Hung MC;Yu D
• 通讯作者: Yu D