Estrogen Receptor and NFkB Crosstalk in Breast Cancer

乳腺癌中的雌激素受体和 NFkB 串扰

• 批准号: 9189694
• 负责人: Jonna Frasor
• 金额: $ 48.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-04 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9189694
• 关键词: Affect; Alpha Cell; Aromatase Inhibitors; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer cell line; Cell physiology; Cells; Cessation of life; Collection; Data; Development; Diagnosis; Disease; Disease Progression; Endocrine; Estrogen Receptor alpha; Estrogen Receptors; Estrogen receptor positive; Failure; Gene Expression Profile; Gene Targeting; Genes; Goals; In Vitro; Inflammatory; Link; Maintenance; Mammary Neoplasms; Mammospheres; Mediator of activation protein; Molecular; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phenotype; Population; Property; Recurrence; Recurrent tumor; Relapse; Resistance; Resistance development; Risk; Role; Selective Estrogen Receptor Modulators; Survival Rate; Tamoxifen; Testing; Treatment Efficacy; Tumor Initiators; Tumor-Derived; Woman; Work; base; disorder subtype; genetic signature; hormone therapy; in vivo; malignant breast neoplasm; new therapeutic target; novel; novel therapeutic intervention; platelet protein P47; prevent; public health relevance; response; self-renewal; stem; stem-like cell; transcription factor; tumor; tumor xenograft

 DESCRIPTION (provided by applicant): Up to 75% of breast tumors are estrogen receptor (ER) positive and nearly 50% of these will recur following endocrine therapy. Thus, new therapeutic targets and strategies are urgently needed for a large population of women. Our work demonstrates that ER and NFB interact cooperatively to synergistically up-regulate a gene signature that (i) is correlated with the more aggressive, Luminal B phenotype of ER+ breast cancer and (ii) predicts an increased risk of recurrence for women given endocrine therapy. Moreover, our preliminary studies suggest that an expansion of the "stem-like" or "tumor-initiating" cell (BCSC) population is a response to increased ER/NFB crosstalk resulting in TAM-resistance and subsequent tumor recurrence. We found that ER/NFB crosstalk i) increases expression of multiple genes associated with BCSCs, ii) promotes expansion of a cell population expressing BCSC markers, and iii) enhances mammosphere formation, a functional readout of BCSC activity. Importantly, we identified PHLDA1 (Pleckstrin homology-like domain A1) as a key ER/NFB target gene that is not only necessary for these phenotypes but is also up-regulated in both isolated BCSCs and ER+ tumors in patients that respond poorly to TAM. Based on these findings, we hypothesize that the coordinated activity of ER and NFB promotes expansion of the BCSC population in ER+ breast cancers and that this drives progression to a TAM-resistant and recurrent phenotype. Moreover, we propose ER/NFB target genes, such as PHLDA1, are critical mediators of these ER/NFB driven phenotypes. In Aim 1, we will test the hypothesis that ER/NFB cooperatively enables expansion of the BCSC population in ER+ breast cancer cell lines and patient-derived tumors. Whether this expansion is through BCSC self-renewal and is BCSC-intrinsic will be investigated. In Aim 2, we will investigate how activation of the ER/NFB axis in breast cancer cells and tumors promotes the development of SERM resistance in vitro and tumor recurrence in vivo. Whether depletion or targeting of BCSCs can prevent TAM resistance and tumor recurrence will be investigated. And in Aim 3, we will identify critical ER/NFkB crosstalk genes, such as PHLDA1, that are necessary for the maintenance and/or expansion of the BCSC population of ER+ breast cancers. Whether these factors also contribute to the development of SERM resistance and tumor recurrence will be determined. From the proposed studies, we expect to provide the rationale for developing new and effective therapeutic strategies to target ER-NFB crosstalk and BCSC activity in ER+ tumors. Our long-term goal is to use these strategies to prevent tumor relapse and progression in women with ER+ breast cancers on endocrine therapy.

 描述（申请人提供）：高达 75% 的乳腺肿瘤是雌激素受体（ER）阳性，其中近 50% 在内分泌治疗后会复发，因此，大量女性迫切需要新的治疗靶点和策略。我们的工作表明，ER 和 NFB 协同相互作用，协同上调基因特征，该基因特征 (i) 与 ER+ 乳腺癌更具侵袭性的 Luminal B 表型相关，并且 (ii)此外，我们的初步研究表明，“干细胞样”或“肿瘤起始”细胞 (BCSC) 群体的扩张是对 ER/NFκB 串扰增加的反应。我们发现 ER/NF+B 串扰 i) 增加与 BCSC 相关的多个基因的表达，ii) 促进表达 BCSC 标记的细胞群的扩张，以及iii) 增强乳腺球形成，这是 BCSC 活性的功能读数。重要的是，我们确定 PHLDA1（Pleckstrin 同源样结构域 A1）是关键的 ER/NFκB 靶基因，它不仅是这些表型所必需的，而且还被上调。在对 TAM 反应不佳的患者中分离的 BCSC 和 ER+ 肿瘤中，基于这些发现，我们发现 ER 和 NFκB 的协调活性促进了 BCSC 的扩张。 In Aim 认为 ER+ 乳腺癌人群，这会导致 TAM 耐药和复发表型的进展。在图 1 中，我们将检验 ER+ 乳腺癌细胞系和患者源性肿瘤中 ER/NF+B 协同扩增 BCSC 群体的假设，这种扩增是否是通过 BCSC 自我更新实现的。在目标 2 中，我们将研究乳腺癌细胞和肿瘤中 ER/NF-B 轴的激活如何促进体外 SERM 耐药性的发展以及体内肿瘤复发。 BCSC 可以预防 TAM 耐药和肿瘤复发，并且在目标 3 中，我们将鉴定关键的 ER/NFkB 串扰基因，例如 PHLDA1，它们对于维持和/或扩展 TAM 是必需的。我们将确定这些因素是否也会导致 SERM 耐药和肿瘤复发的发生，从而为开发针对 ER-NF 的新的有效治疗策略提供依据。 ER+ 肿瘤中的 B 串扰和 BCSC 活性我们的长期目标是使用这些策略来预防接受内分泌治疗的 ER+ 乳腺癌女性的肿瘤复发和进展。