Stromal activation in the progression of high ErbB2/1433zeta DCIS to IBC

高 ErbB2/1433zeta DCIS 进展为 IBC 过程中的基质激活

• 批准号: 8678864
• 负责人: Dihua Yu
• 金额: $ 25.83万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678864
• 关键词: Academy; Affect; Biological; Breast Cancer Cell; Breast Cancer Early Detection; Breast Epithelial Cells; CCL2 gene; Cessation of life; Clinical Management; Clinical Trials; Country; Data; Development; Diagnostic; Doctor of Philosophy; Epigenetic Process; Event; Extracellular Matrix; FGF2 gene; Fibroblasts; Funding; Future; Genes; Genetic; Goals; Growth Factor; Human; In Situ; In Situ Lesion; Institute of Medicine (U.S.); Intervention; Investigation; Lead; Life; Light; Lung; MCF10A cells; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Messenger RNA; Molecular; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Pathway interactions; Patient Care; Patients; Performance; Play; Recurrence; Research; Research Institute; Research Priority; Role; Sampling; Staging; Testing; Transgenic Mice; Woman; cDNA Arrays; cancer cell; chemokine; clinically relevant; cohort; comparative effectiveness; cytokine; early onset; effective intervention; effectiveness research; high risk; improved; infiltrating duct carcinoma; innovation; insight; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; overexpression; prevent; prognostic; tool; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Studying the transition from non-invasive ductal carcinoma in situ (DCIS) to life-threatening invasive breast cancer (IBC) is listed in the top quartile of the 100 research priorities by the Institute of Medicine of the National Academies. This proposal explores innovative ways to better understand how early stage DCIS progresses to IBC. We recently found that when a DCIS lesion highly expresses two genes (ErbB2 and 14-3-3?), they readily progress to IBC, and we have identified key molecular alterations in tumor cells contributing to this progression to IBC with increased invasion. However, breast cancer progression is not a "solo" performance of tumor cells. It evolves as the result of sophisticated interaction between tumor cells and their surrounding microenvironment stromal components. Indeed, our preliminary data indicate that ErbB2 and 14-3-3? co-overexpressing mammary tumor cells dynamically interact with and activate stroma during tumor progression. Therefore, we hypothesize that ErbB2/14-3-3? co-overexpressing breast cancer cells alter their stromal components and convert normal stroma (tumor suppressive) to activated stroma (tumor- promoting), which reciprocally provide a permissive microenvironment to promote progression from DCIS to IBC. Here, we propose three Specific Aims to explore the roles of stroma activation in the progression of ErbB2/1433? co-overexpressing DCIS to IBC using mammary gland-specific 14-3- 3?.neu bitransgenic mouse models, human MECs, and patients' breast tumor samples. We will 1) Determine the effects of ErbB2 and 14-3-3? co-overexpression in mammary tumors on their stroma, and the contribution of activated stroma to tumor progression and metastasis; 2) Investigate the molecular mechanisms by which ErbB2 and 14-3-3? co-overexpressing mammary tumors induce stromal activation; 3) Examine the clinical relevance of stromal activation in ErbB2/1433?+++ DCIS from patients and its association with progression to IBC and metastatic breast cancer. Significantly, these proposed studies on the functional impact and mechanisms of the reciprocal interactions between ErbB2/14-3-3? co-overexpressing breast tumor cells and their dynamic stromal microenvironment will bring exciting new biological insights on how DCIS progressing to IBC and may impact on the clinical management of patients. This could open a new venue for development of future strategies to reverse the tumor-enhancing effects of the activated stroma by re-establishing a suppressive microenvironment to effectively prevent or reverse the deadly transition of DCIS to IBC.

描述（由申请人提供）：研究从非侵入性导管癌（DCIS）到威胁生命的侵入性乳腺癌（IBC）的过渡，已由国家学院医学研究所的100个研究优先级的顶级四分位数中列出。 该建议探讨了创新的方法，以更好地了解DCI的早期阶段如何发展到IBC。 我们最近发现，当DCIS病变高度表达两个基因（ERBB2和14-3-3？）时，它们很容易发展到IBC，并且我们已经确定了肿瘤细胞中的关键分子改变，从而增加了IBC的进展，并增加了侵袭。 但是，乳腺癌的进展不是肿瘤细胞的“独奏”性能。 它是由于肿瘤细胞及其周围微环境基质成分之间的复杂相互作用而演变的。 确实，我们的初步数据表明ERBB2和14-3-3？共表达乳腺肿瘤细胞在肿瘤进展过程中与基质动态相互作用并激活基质。 因此，我们假设ERBB2/14-3-3？共表达的乳腺癌细胞改变其基质成分，并将正常的基质（肿瘤抑制）转化为活化的基质（肿瘤促进），后者相互提供宽松的微环境，以促进从DCIS到IBC的发展。 在这里，我们提出了三个特定的目的，以探索基质激活在ERBB2/1433进展中的作用？使用乳腺特异性14-3-3？.NEU BITRANSGENIC小鼠模型，人MEC和患者的乳腺肿瘤样品将DCI共表达DCI。 我们将确定ERBB2和14-3-3的影响？乳腺肿瘤在基质上的共同表达，以及活化基质对肿瘤进展和转移的贡献； 2）研究ERBB2和14-3-3的分子机制？共表达乳腺肿瘤会诱导基质激活； 3）检查患者的ERBB2/1433？+++ DCI中基质激活的临床相关性及其与IBC和转移性乳腺癌的相关性。 值得注意的是，这些提出的关于ERBB2/14-3-3之间相互作用的功能影响和机制的研究？共表达乳腺肿瘤细胞及其动态基质微环境将为DCIS如何发展到IBC，并可能影响患者的临床管理。 这可以为开发未来的策略开发一个新的场所，以扭转激活基质的肿瘤增强作用，通过重新建立抑制性的微环境，以有效防止或扭转DCI到IBC的致命过渡。