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。

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.