Lim Elgene, Vaillant François, Wu Di, Forrest Natasha C, Pal Bhupinder, Hart Adam H, Asselin-Labat Marie-Liesse, Gyorki David E, Ward Teresa, Partanen Audrey, Feleppa Frank, Huschtscha Lily I, Thorne Heather J, Fox Stephen B, Yan Max, French Juliet D, Brown Melissa A, Smyth Gordon K, Visvader Jane E, Lindeman Geoffrey J
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Nat Med. 2009 Aug;15(8):907-13. doi: 10.1038/nm.2000. Epub 2009 Aug 2.
Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .
携带编码肿瘤抑制蛋白BRCA1的BRCA1基因突变的女性所患的基底样乳腺癌，被认为是由乳腺干细胞发展而来。为了探究BRCA1基因突变携带者早期发生的细胞变化，我们前瞻性地从正常乳腺组织以及BRCA1基因突变杂合个体的癌前标本中分离出不同的上皮亚群。我们描述了三种上皮亚群，包括基底干细胞/祖细胞、管腔祖细胞和成熟管腔细胞。出乎意料的是，我们发现BRCA1基因突变携带者的乳腺组织中管腔祖细胞群体有所扩大，该群体在体外表现出因子非依赖性生长。此外，基因表达谱分析显示，BRCA1基因突变杂合的乳腺组织和基底样乳腺癌与正常管腔祖细胞的相似性高于任何其他亚群，包括富含干细胞的群体。c-KIT酪氨酸激酶受体（由KIT编码）成为管腔祖细胞的关键标志物，并且在BRCA1相关的癌前组织和肿瘤中表达更高。我们的研究结果表明，异常的管腔祖细胞群体是BRCA1相关基底样肿瘤发生转化的靶点。
