Estrogen Receptor and NFkB Crosstalk in Breast Cancer

美国将有超过23万名女性被诊断出患有乳腺癌，近4万人将死于 每年都有疾病。大多数乳腺肿瘤表达雌激素受体α(ER)，约占全部乳腺肿瘤的70-80%。 患有ER+肿瘤的女性通常接受内分泌治疗(ET)，如芳香酶抑制剂或他莫昔芬 ()。虽然最初的存活率总体上是好的，但据估计，~40%的ER+肿瘤将复发， 其中近一半在完成标准的5年佐剂ET治疗后复发。这种晚期复发的风险 这表明在许多情况下，一群肿瘤细胞可以持续或耐受ET制剂，只会对 一旦ET完成，就复发。这一结论得到了几项研究的支持，这些研究表明，10年的ET是 比5年更好。在研究对ET选择性压力的早期反应可能如何有助于ET耐受的研究中， 我们发现，在接受新辅助治疗的ER+乳腺肿瘤患者中，NFB的激活是一种常见事件 ET，以及ER+乳腺癌细胞系、患者来源的有机化合物和异种移植瘤中也有表达。此时将显示此激活 是NFB+乳腺癌细胞扩增的结果，尽管ET仍能增殖并持续存在 治疗。重要的是，抑制NFB可以防止复发，这是由缺乏细胞和 肿瘤一旦治疗终止。此外，我们还发现，从ET耐受中衍生出的一个基因特征 在ER+疾病患者中，细胞与高肿瘤分级和增加复发风险有关。基座 根据这些发现，我们假设ET的选择压力允许NFB+，ET- 耐受细胞群体和针对这些群体的治疗将防止复发和疾病 进步。为了测试这一点，我们提出了三个目标：目标1.确定ER+乳腺中耐受ET的细胞群 目的2.确定核因子B在内毒素耐受中的调节和作用机制；以及目的3。 目的：研究靶向ET耐受细胞群的后果。为了达到这些目标，我们将 在短期选择性压力下对ET治疗早期临床前模型进行单细胞RNA-SEQ ET和随着时间的推移适应性抵抗力的发展。然后我们将调查这些种群的持久性 在ET耐药的临床前模型中，并在人类原发和转移肿瘤中验证我们的发现。我们会 还要检验这样一种假设，即ET耐受细胞中的NFB活性是对由 ET的选择性压力，以及对这种细胞应激的保护性作用。此外，我们还将使用 互补的基因和小分子抑制因子B途径的抑制剂，以及KEY的抑制剂 NFB调节器和效应器，以测试ET耐受细胞在复发和疾病进展中的作用，使用两者 免疫缺陷小鼠患者来源的肿瘤和免疫活性小鼠模型。成功者 这些目标的完成将确立：1)核因子B在促进ET耐受和疾病复发方面的新作用 ER+乳腺癌的研究，II)对NFB在促进ET耐受中的作用的机制的洞察，以及III)新的 针对ET耐受细胞的策略，以防止ER+乳腺癌的复发。

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.