NFIA调控肿瘤祖细胞参与乳腺癌内分泌治疗耐药的机制研究

Tamoxifen is the most commonly used treatment for patients with oestrogen receptor (ER)-positive breast cancer. Although many patients benefit from tamoxifen, resistance is an important clinical problem and its mechanism hasn’t been fully elucidated. Our previous study found the proportion of luminal progenitor cells but bot stem cells was increased in tamoxifen resistant breast cancer cells and luminal progenitor cells are more resistant to tamoxifen than mature luminal cells. We screened the tamoxifen resistance related genes and found NFIA was upregulated in luminal progenitor cells and regulated the reactivity of luminal progenitor cells to tamoxifen. Thus, we will propose that luminal progenitor cells instead of stem cells are the target subpopulation for endocrine therapy resistance.And NFIA is the key protein in regulating luminal progenitor cells-mediated tamoxifen resistance. In this project, we will first detect the biological properies of luminal progenitors in the fields of self-renewal, differentiation and tumorigenesis. Then we’ll investigated the mechanism of NFIA regulated luminal progenitor cell-mediated tamoxifen resistance by using in vitro cell biological experiments, xenograft animal model and clinical data analysis. This study aims to obtain the solid proofs that luminal progenitor cells are the key subpopulation responsible for endocrine therapy resistance. Our study will provide new target cell subpopulation and target genes to improve the resistance to endocrine therapy of breast cancer.

内分泌治疗耐药已成为亟待解决的临床难题，其机制尚未充分阐明。我们前期的研究发现乳腺肿瘤luminal祖细胞而不是干细胞在他莫西芬耐受的乳腺肿瘤细胞中比例增高，并且luminal祖细胞对他莫西芬治疗抵抗。筛选luminal祖细胞耐药相关基因发现NFIA在祖细胞中表达上调并且与耐药相关。由此，我们提出假设luminal祖细胞而不是干细胞是乳腺癌内分泌耐药的靶细胞，并且NFIA调控了luminal祖细胞的耐药过程。本项目拟在前期工作的基础上首先从自我更新、分化和成瘤能力等方面检测luminal祖细胞的生物学特性。进一步结合体外细胞实验、移植瘤模型动物实验及临床资料分析研究NFIA调控luminal祖细胞参与内分泌耐药的机制。本研究旨在获得luminal祖细胞是引起乳腺癌内分泌治疗耐药的关键细胞亚群的可靠证据，研究结果将为改善临床乳腺癌内分泌治疗耐药的状况提供新的靶细胞和靶分子。

ER+乳腺癌占所有乳腺癌患者的50-70%，内分泌治疗是这类乳腺癌的主要治疗方式，然而约有三分之一的患者最终会发生耐药，进展为晚期乳腺癌，因此研究内分泌耐药的机制具有重要的科学价值和临床意义。本项目从多层面探索导致内分泌耐药的亚细胞群体和耐药相关分子，发现了luminal祖细胞具有同干细胞相似的特性，对他莫昔芬治疗耐受。进一步揭示了N1 作为转录因子通过调控下游F9和I5的表达，分别调控luminal祖细胞的分化和增殖，进而导致内分泌耐药的发生。除此以为，本项目还探讨了lncRNA在调控内分泌耐药中的作用，并分析他莫昔芬耐药患者对化疗和去乙酰化酶抑制剂等其他治疗方式的敏感性和治疗指征。本项目不仅为临床逆转或预防他莫昔芬耐药提供靶点，还为已经发生耐药的患者提供其他治疗选择的依据。