Breast tumors display tremendous heterogeneity in part due to varying molecular alterations, divergent cells of origin, and differentiation. Understanding where and how this heterogeneity develops is likely important for effective breast cancer eradication. Insulin-like growth factor (IGF) signaling is critical for normal mammary gland development and function, and has an established role in tumor development and resistance to therapy. Here we demonstrate that constitutive activation of the IGF1 receptor (IGF1R) influences lineage differentiation during mammary tumorigenesis. Transgenic IGF1R constitutive activation promotes tumors with mixed histologies, multiple cell lineages and an expanded bi-progenitor population. In these tumors, IGF1R expands the luminal-progenitor population while influencing myoepithelial differentiation. Mammary gland transplantation with IGF1R-infected mammary epithelial cells (MECs) resulted in hyperplastic, highly differentiated outgrowths and attenuated reconstitution. Restricting IGF1R constitutive activation to luminal versus myoepithelial lineage-sorted MECs resulted in ductal reconstitutions co-expressing high IGF1R levels in the opposite lineage of origin. Using in vitro models, IGF1R constitutively activated MCF10A cells showed increased mammosphere formation and CD44+/CD24-population, which was dependent upon Snail and NFκB signaling. These results suggest that IGF1R expands luminal progenitor populations while also stimulating myoepithelial cell differentiation. This ability to influence lineage differentiation may promote heterogeneous mammary tumors, and have implications for clinical treatment.

中文翻译：

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IGF1R的组成性激活可扩大乳腺祖细胞并影响乳腺肿瘤发生过程中的谱系分化。

乳腺肿瘤表现出巨大的异质性，部分原因是分子的变化，起源细胞的分化和分化。了解异质性在何处以及如何发展对于有效根除乳腺癌可能很重要。胰岛素样生长因子（IGF）信号对于正常的乳腺发育和功能至关重要，并且在肿瘤的发展和对治疗的抵抗力中具有确定的作用。在这里，我们证明了IGF1受体（IGF1R）的组成性激活会影响乳腺肿瘤发生过程中的谱系分化。转基因IGF1R组成型激活可促进具有混合组织学，多种细胞谱系和扩大的双祖细胞群的肿瘤。在这些肿瘤中，IGF1R在影响肌上皮分化的同时扩大了管腔祖细胞群。用IGF1R感染的乳腺上皮细胞（MEC）进行乳腺移植会导致增生，高度分化的产物和减弱的重建。将IGF1R组成型激活限制在管腔与肌上皮谱系分类的MEC之间导致导管重构在相反谱系中共表达高IGF1R水平。使用体外模型，IGF1R组成型激活的MCF10A细胞表现出增加的乳球形成和CD44 + / CD24种群，这取决于Snail和NFκB信号传导。这些结果表明，IGF1R扩大了管腔祖细胞群，同时也刺激了肌上皮细胞的分化。影响谱系分化的这种能力可能会促进异质性乳腺肿瘤，并对临床治疗产生影响。