Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Bryan, TX, USA.
Biomedical Sciences Graduate Program, Texas A&M University College of Medicine, College Station, TX, USA.
Stem Cells. 2022 Mar 31;40(3):273-289. doi: 10.1093/stmcls/sxab018.
Insulin-like growth factor I (IGF-1) has been implicated in breast cancer due to its mitogenic and anti-apoptotic effects. Despite substantial research on the role of IGF-1 in tumor progression, the relationship of IGF-1 to tissue stem cells, particularly in mammary tissue, and the resulting tumor susceptibility has not been elucidated. Previous studies with the BK5.IGF-1 transgenic (Tg) mouse model reveals that IGF-1 does not act as a classical, post-carcinogen tumor promoter in the mammary gland. Pre-pubertal Tg mammary glands display increased numbers and enlarged sizes of terminal end buds, a niche for mammary stem cells (MaSCs). Here we show that MaSCs from both wild-type (WT) and Tg mice expressed IGF-1R and that overexpression of Tg IGF-1 increased numbers of MaSCs by undergoing symmetric division, resulting in an expansion of the MaSC and luminal progenitor (LP) compartments in pre-pubertal female mice. This expansion was maintained post-pubertally and validated by mammosphere assays in vitro and transplantation assays in vivo. The addition of recombinant IGF-1 promoted, and IGF-1R downstream inhibitors decreased mammosphere formation. Single-cell transcriptomic profiles generated from 2 related platforms reveal that IGF-1 stimulated quiescent MaSCs to enter the cell cycle and increased their expression of genes involved in proliferation, plasticity, tumorigenesis, invasion, and metastasis. This study identifies a novel, pro-tumorigenic mechanism, where IGF-1 increases the number of transformation-susceptible carcinogen targets during the early stages of mammary tissue development, and "primes" their gene expression profiles for transformation.
胰岛素样生长因子 I（IGF-1）因其有丝分裂和抗细胞凋亡作用而与乳腺癌有关。尽管对 IGF-1 在肿瘤进展中的作用进行了大量研究，但 IGF-1 与组织干细胞的关系，特别是在乳腺组织中的关系，以及由此产生的肿瘤易感性尚未阐明。BK5.IGF-1 转基因（Tg）小鼠模型的先前研究表明，IGF-1 不会在乳腺中充当经典的、致癌物后的肿瘤促进剂。青春期前的 Tg 乳腺显示出末端芽的数量增加和大小增大，末端芽是乳腺干细胞（MaSCs）的一个龛位。在这里，我们表明，来自 WT 和 Tg 小鼠的 MaSCs 都表达 IGF-1R，并且 Tg IGF-1 的过表达通过对称分裂增加 MaSCs 的数量，导致青春期前雌性小鼠中的 MaSC 和腔前体（LP）区室扩张。这种扩张在青春期后得到维持，并通过体外类乳腺球体形成实验和体内移植实验进行了验证。重组 IGF-1 的添加促进了乳腺球体的形成，而 IGF-1R 下游抑制剂则减少了乳腺球体的形成。来自 2 个相关平台的单细胞转录组谱表明，IGF-1 刺激静止的 MaSCs 进入细胞周期，并增加了它们参与增殖、可塑性、肿瘤发生、侵袭和转移的基因的表达。这项研究确定了一种新的促肿瘤发生机制，其中 IGF-1 在乳腺组织发育的早期阶段增加了易转化的致癌物靶细胞的数量，并“启动”了它们的基因表达谱以进行转化。
