BRCA1 mutation influences progesterone response in human benign mammary organoids
BRCA1 mutation influences progesterone response in human benign mammary organoids
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DOI：
10.1186/s13058-019-1214-0
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发表时间：
2019-11-26
影响因子：
7.4
通讯作者：
Kim, J. Julie
中科院分区：
文献类型：
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作者：
Davaadelger, Batzaya;Choi, Mi-Ran;Kim, J. Julie
背景 携带种系 BRCA1 基因突变的女性一生中患乳腺癌的风险显着增加。虽然 BRCA1 携带者经常出现三阴性、基底细胞样、侵袭性乳腺肿瘤，但激素信号传导在 BRCA1 突变乳腺癌的发生过程中非常重要。我们使用体外类器官系统研究了 BRCA1 突变良性乳腺组织中的激素反应。方法 从非携带者或 BRCA1 突变携带者的良性乳腺组织中产生的无支架、多细胞人类乳腺类器官，在体外采用雌二醇 (E2) 和孕酮 (P4) 的逐步月经周期激素方案进行 28 天的治疗。结果乳腺类器官表现出天然乳腺组织的特征，包括激素受体的表达、胶原蛋白的产生以及管腔和基底上皮以及基质成纤维细胞的标记。 RNA测序分析揭示了非携带者和BRCA1突变类器官对激素治疗的不同基因表达反应。选择性黄体酮受体调节剂醋酸特拉司酮 (TPA) 用于识别特异性 PR 调节基因。具体来说，在 BRCA1 突变的类器官中，细胞外基质组织基因受到 E2+P4+TPA 的调节，但在非载体类器官中则不受 E2+P4+TPA 的调节。相反，在非载体类器官中，已知的 PR 靶基因（例如细胞周期基因）被 TPA 抑制。结论 这些数据表明，BRCA1 突变影响激素反应，特别是 PR 活性，这与非载体类器官不同。我们的类器官模型系统揭示了 PR 在 BRCA1 突变良性乳腺细胞中的作用以及修饰激素受体 (HR) 阴性细胞的关键旁分泌作用的重要见解。使用该模型系统有必要进一步分析 BRCA1 和 PR 串扰的分子机制。
Background Women, who carry a germline BRCA1 gene mutation, have a markedly increased risk of developing breast cancer during their lifetime. While BRCA1 carriers frequently develop triple-negative, basal-like, aggressive breast tumors, hormone signaling is important in the genesis of BRCA1 mutant breast cancers. We investigated the hormone response in BRCA1-mutated benign breast tissue using an in vitro organoid system. Methods Scaffold-free, multicellular human breast organoids generated from benign breast tissues from non-carrier or BRCA1 mutation carriers were treated in vitro with a stepwise menstrual cycle hormone regimen of estradiol (E2) and progesterone (P4) over the course of 28 days. Results Breast organoids exhibited characteristics of the native breast tissue, including expression of hormone receptors, collagen production, and markers of luminal and basal epithelium, and stromal fibroblasts. RNA sequencing analysis revealed distinct gene expression in response to hormone treatment in the non-carrier and BRCA1-mutated organoids. The selective progesterone receptor modulator, telapristone acetate (TPA), was used to identify specifically PR regulated genes. Specifically, extracellular matrix organization genes were regulated by E2+P4+TPA in the BRCA1-mutated organoids but not in the non-carrier organoids. In contrast, in the non-carrier organoids, known PR target genes such as the cell cycle genes were inhibited by TPA. Conclusions These data show that BRCA1 mutation influences hormone response and in particular PR activity which differs from that of non-carrier organoids. Our organoid model system revealed important insights into the role of PR in BRCA1-mutated benign breast cells and the critical paracrine actions that modify hormone receptor (HR)-negative cells. Further analysis of the molecular mechanism of BRCA1 and PR crosstalk is warranted using this model system.