Estrogen Receptor and NFkB Crosstalk in Breast Cancer

美国将有超过23万名妇女被诊断患有乳腺癌，近4万人将死于乳腺癌。 每年的疾病大多数乳腺肿瘤表达雌激素受体α（ER），约占所有病例的70-80%。 ER+肿瘤患者通常接受内分泌治疗（ET），如芳香化酶抑制剂或他莫昔芬 （TAM）。虽然初始存活率通常良好，但估计约40%的ER+肿瘤会复发， 几乎一半在完成标准5年辅助ET后复发。这种晚期复发的风险 表明在许多情况下，肿瘤细胞群可以持续存在或耐受ET药物，只是有助于 一旦完成ET，就会复发。这一结论得到了几项研究的支持，表明10年的ET是 上级至5年在研究对ET选择性压力的早期反应如何有助于ET耐受性时， 我们发现NF κ B B的激活是ER+乳腺肿瘤患者接受新辅助治疗的常见事件， ET以及ER+乳腺癌细胞系、患者来源的类器官和异种移植物中。此激活显示 是NF κ B B+乳腺癌细胞扩增的结果，尽管ET，NF κ B+乳腺癌细胞仍能增殖并持续存在。 治疗重要的是，抑制NF κ B B可防止复发，这是由缺乏细胞再生长决定的， 一旦TAM治疗终止，肿瘤就停止。此外，我们发现来自ET耐受的基因签名， ER+患者的高肿瘤分级和复发风险增加相关。基于 根据这些发现，我们推测ET的选择性压力允许NF κ B B+、ET- 耐受性细胞群，靶向这些群体的治疗将防止复发和疾病 进展为了验证这一点，我们提出了三个目标：目标1。确定ER+乳腺癌中的ET耐受细胞群 癌症模型;目标2.探讨NF κ B B在ET耐受中的调节和作用机制; 研究靶向ET耐受细胞群的后果。为了实现这些目标，我们将 在短期选择性压力下，对ET治疗初治的临床前模型进行单细胞RNA-seq ET和随着时间的推移，适应性阻力的发展。然后我们将研究这些种群的持久性 在ET耐药的临床前模型中，并验证我们在人类原发性和转移性肿瘤中的发现。我们将 我们还检验了这样一种假设，即ET耐受细胞中的NF κ B B活性是对细胞应激的反应， ET的选择性压力，以及对细胞应激的保护作用。此外，我们将使用 抑制NF κ B B途径的互补遗传和小分子抑制剂，以及关键的 NF κ B B调节剂和效应物，以测试ET耐受细胞在复发和疾病进展中的作用，使用 免疫功能低下小鼠和免疫活性小鼠模型中的患者来源的肿瘤。成功 这些目标的完成将确立i）NF κ B B在促进ET耐受和疾病复发中的新作用 的ER+乳腺癌，ii）在促进ET耐受性的NF κ B B的功能机制的见解，和iii）新的 靶向ET耐受细胞以预防ER+乳腺癌复发的策略。

More than 230,000 women in the US will be diagnosed with breast cancer and nearly 40,000 will die from the disease annually. The majority of breast tumors express estrogen receptor α (ER), found in ~70-80% of all cases. Women with ER+ tumors typically receive endocrine therapy (ET), such as aromatase inhibitors or tamoxifen (TAM). While initial survival rates are generally good, it is estimated that ~40% of ER+ tumors will relapse, with almost half of these recurring after completing the standard 5 years of adjuvant ET. This risk for late relapse suggests that in many cases a population of tumor cells can persist or tolerate ET agents, only to contribute to relapse once ET is completed. This conclusion is supported by several studies showing that 10 yr of ET is superior to 5 yr. In studying how early responses to the selective pressure of ET might contribute to ET-tolerance, we found that activation of NFB was a common event in ER+ breast tumors of patients treated with neo-adjuvant ET, as well as in ER+ breast cancer cell lines, patient derived organoids, and xenografts. This activation appears to be the result of an expansion of NFB+ breast cancer cells that can proliferate and persist despite ET treatment. Importantly, inhibiting NFB prevents relapse, as determined by the lack of regrowth of cells and tumors once TAM treatment is terminated. Moreover, we found that a gene signature derived from ET-tolerant cells was associated with high tumor grade and increased risk of relapse in patients with ER+ disease. Based on these findings, we hypothesize that the selective pressure of ET allows for the expansion of NFB+, ET- tolerant cell populations and that targeting these populations therapeutically will prevent relapse and disease progression. To test this, we propose three aims: Aim 1. To define ET-tolerant cell populations in ER+ breast cancer models; Aim 2. To determine the mechanism of NFB regulation and action in ET-tolerance; and Aim 3. To investigate the consequences of targeting ET-tolerant cell populations. To address these aims, we will perform single cell RNA-seq on ET-treatment naïve preclinical models under the selective pressure of short-term ET and over time as adaptive resistance develops. We will then investigate the persistence of these populations in preclinical models of ET-resistance and validate our findings in human primary and metastatic tumors. We will also examine the hypothesis that NFB activity in ET-tolerant cells is a response to cellular stress caused by the selective pressure of ET, as well as a protective player in response to that cellular stress. In addition, we will use complementary genetic and small molecule inhibitors that inhibit the NFB pathway, as well as inhibitors of key NFB regulators and effectors, to test the role of ET-tolerant cells in relapse and disease progression, using both patient-derived tumors in immunocompromised mice and an immunocompetent mouse model. The successful completion of these aims will establish i) a novel role for NFB in promoting ET-tolerance and disease relapse of ER+ breast cancer, ii) mechanistic insight into the function of NFB in promoting ET tolerance, and iii) novel strategies to target ET-tolerant cells to prevent recurrence of ER+ breast cancer.