Accumulation of multipotent progenitors with a basal differentiation bias during aging of human mammary epithelia.
Accumulation of multipotent progenitors with a basal differentiation bias during aging of human mammary epithelia.
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DOI：
10.1158/0008-5472.can-12-0157
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发表时间：
2012-07-15
期刊：
影响因子：
11.2
通讯作者：
Labarge MA
中科院分区：
文献类型：
--
作者：
Garbe JC;Pepin F;Pelissier FA;Sputova K;Fridriksdottir AJ;Guo DE;Villadsen R;Park M;Petersen OW;Borowsky AD;Stampfer MR;Labarge MA
50岁以上的女性占新发乳腺癌诊断的75%，并且这些肿瘤中的大多数是管腔亚型。尽管与年龄相关的变化，包括内分泌特征和乳腺微环境的改变，会增加癌症风险，但对这些观察结果背后的分子机制缺乏了解。在这项研究中，我们从16至91岁的女性中收集了大量来自原代组织的正常人乳腺上皮细胞株，以研究衰老乳腺细胞中发生的分子变化。我们发现，在有限寿命的培养和未培养的上皮细胞中，衰老与肌上皮细胞的减少和表达角蛋白14和整合素α6的管腔细胞的增加有关，角蛋白14和整合素α6是一种通常仅在30岁以下女性的肌上皮细胞中表达的表型。管腔谱系的变化是由有缺陷的多能祖细胞的年龄依赖性扩增引起的，这些祖细胞产生不完全分化的管腔或肌上皮细胞。因此，衰老过程导致管腔/肌上皮谱系平衡的转变和多能祖细胞功能谱的变化，这两者一起增加了恶性转化的可能性。总之，我们的研究结果提供了一个细胞基础来解释观察到的乳腺癌的脆弱性，随着年龄的增长。
Women over 50 years of age account for 75% of new breast cancer diagnoses, and the majority of these tumors are of a luminal subtype. Although age-associated changes, including endocrine profiles and alterations within the breast microenvironment, increase cancer risk, an understanding of the molecular mechanisms that underlie these observations is lacking. In this study, we generated a large collection of normal human mammary epithelial cell strains from women aged 16 to 91 years, derived from primary tissues, to investigate the molecular changes that occur in aging breast cells. We found that in finite-lifespan cultured and uncultured epithelial cells, aging is associated with a reduction of myoepithelial cells and an increase in luminal cells that express keratin 14 and integrin α6, a phenotype that is usually expressed exclusively in myoepithelial cells in women under 30. Changes to the luminal lineage resulted from age-dependent expansion of defective multipotent progenitors that gave rise to incompletely differentiated luminal or myoepithelial cells. The aging process therefore results in both a shift in the balance of luminal/myoepithelial lineages and to changes in the functional spectrum of multipotent progenitors, which together increase the potential for malignant transformation. Together, our findings provide a cellular basis to explain the observed vulnerability to breast cancer that increases with age.