Área de Investigaciones, Instituto de Oncología, "Ángel H. Roffo", Av. San Martín 5481, Buenos Aires C1417DTB, Argentina.
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Cells. 2020 Sep 11;9(9):2074. doi: 10.3390/cells9092074.
To investigate the role of PR isoforms on the homeostasis of stem cells in the normal and neoplastic mammary gland, we used PRA and PRB transgenic mice and the T47D human breast cancer cell line and its derivatives, T47D YA and YB (manipulated to express only PRA or PRB, respectively). Flow cytometry and mammosphere assays revealed that in murine breast, overexpression of PRB leads to an increase in luminal and basal progenitor/stem cells. Ovariectomy had a negative impact on the luminal compartment and induced an increase in mammosphere-forming capacity in cells derived from WT and PRA mice only. Treatment with ICI 182,780 augmented the mammosphere-forming capacity of cells isolated from WT and PRA mice, whilst those from PRB remained unaltered. T47D YB cells showed an increase in the CD44/CD24 subpopulation; however, the number of tumorspheres did not vary relative to T47D and YA, even though they were larger, more irregular, and had increased clonogenic capacity. T47D and YA tumorspheres were modulated by estrogen/antiestrogens, whereas YB spheres remained unchanged in size and number. Our results show that alterations in PR isoform balance have an impact on normal and tumorigenic breast progenitor/stem cells and suggest a key role for the B isoform, with implications in response to antiestrogens.
为了研究 PR 异构体在正常和肿瘤乳腺干细胞自稳态中的作用，我们使用了 PRA 和 PRB 转基因小鼠以及 T47D 人乳腺癌细胞系及其衍生物 T47D YA 和 YB（分别操纵以仅表达 PRA 或 PRB）。流式细胞术和乳腺球体测定显示，在小鼠乳腺中，PRB 的过表达导致腔和基底祖细胞/干细胞增加。卵巢切除术对腔室有负面影响，并仅在 WT 和 PRA 小鼠来源的细胞中诱导乳腺球体形成能力增加。用 ICI 182,780 处理增强了从 WT 和 PRA 小鼠分离的细胞的乳腺球体形成能力，而来自 PRB 的细胞则保持不变。T47D YB 细胞中 CD44/CD24 亚群增加；然而，相对于 T47D 和 YA，肿瘤球体的数量没有变化，尽管它们更大、更不规则且具有更高的克隆形成能力。T47D 和 YA 肿瘤球体受雌激素/抗雌激素调节，而 YB 球体的大小和数量保持不变。我们的结果表明，PR 异构体平衡的改变对正常和致瘤性乳腺祖细胞/干细胞有影响，并表明 B 异构体在对抗雌激素的反应中起关键作用。
