Estrogen Receptor and NFkB Crosstalk in Breast Cancer

 描述（由申请人提供）：高达75%的乳腺肿瘤为雌激素受体（ER）阳性，其中近50%在内分泌治疗后会复发。因此，迫切需要新的治疗目标和战略，为广大妇女。我们的工作表明，ER和NF κ B B相互作用，协同上调基因签名，（i）与ER+乳腺癌的更具侵袭性的Luminal B表型相关，（ii）预测接受内分泌治疗的女性复发风险增加。此外，我们的初步研究表明，“干细胞样”或“肿瘤起始”细胞（BCSC）群体的扩增是对增加的ER/NF κ B B串扰的响应，导致TAM抗性和随后的肿瘤复发。我们发现ER/NF κ B B串扰i）增加与BCSC相关的多个基因的表达，ii）促进表达BCSC标志物的细胞群的扩增，和iii）增强乳腺球形成，BCSC活性的功能读数。重要的是，我们鉴定了PHLDA 1（Pleckstrin同源样结构域A1）作为关键的ER/NF κ B B靶基因，其不仅是这些表型所必需的，而且在对TAM反应差的患者中在分离的BCSC和ER+肿瘤中上调。基于这些发现，我们假设ER和NF κ B B的协同活性促进了ER+乳腺癌中BCSC群体的扩增，并且这推动了向TAM耐药和复发表型的进展。此外，我们提出ER/NF κ B B靶基因，如PHLDA 1，是这些ER/NF κ B B驱动的表型的关键介质。在目的1中，我们将检验ER/NF κ B B协同使得BCSC群体能够在ER+乳腺癌细胞系和患者来源的肿瘤中扩增的假设。这种扩张是否是通过BCSC自我更新，是BCSC内在的将被调查。在目的2中，我们将研究乳腺癌细胞和肿瘤中ER/NF κ B B轴的激活如何促进体外SERM抗性的发展和体内肿瘤复发。将研究BCSC的耗尽或靶向是否可以预防TAM抗性和肿瘤复发。在目标3中，我们将确定关键的ER/NFkB串扰基因，如PHLDA 1，这是维持和/或扩增ER+乳腺癌BCSC群体所必需的。这些因素是否也有助于SERM耐药和肿瘤复发的发展将被确定。从所提出的研究中，我们期望为开发新的和有效的治疗策略提供理论基础，以靶向ER+肿瘤中的ER-NF κ B 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。

 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.