Melchor Lorenzo, Benítez Javier
Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Centre (CNIO), Madrid E-28029, Spain.
Carcinogenesis. 2008 Aug;29(8):1475-82. doi: 10.1093/carcin/bgn157. Epub 2008 Jul 1.
Do breast cancer tumours have a common cell origin? Do different breast cancer molecular phenotypes arise from distinct cell types? The studies we have performed during the last few years in familial breast tumours (BRCA1, BRCA2 and non-BRCA1/2) widen questions about the development of sporadic breast cancer to hereditary breast cancer. Array-comparative genomic hybridisation (CGH) studies show universal genomic aberrations in both familial and sporadic breast cancer subtypes that may be selected in the breast tumour development. The inactivation of BRCA1 seems to play a critical role in oestrogen receptor (ER)-negative cancer stem cells (CSCs), driving the tumour development mostly towards a basal-like or, in some cases, to a luminal B phenotype, but other carcinogenetic events are proposed to explain the remaining tumour subtypes. The existence of common genomic alterations in basal-like, ERBB2 and luminal B breast tumours may suggest a common cell origin or clonal selection of these tumour subtypes, arising from an ER-negative CSC or from a progenitor cell (PC). Finally, specific genomic aberrations in ER-positive tumours could provide cellular proliferation advantages when the cells are exposed to oestrogen. We propose a combination of the CSC hypothesis (for the carcinogenesis processes) and the clonal selection model (in terms of tumour development). We uphold that the basal-like-, ERBB2- and luminal B-sporadic and familial tumour subtypes have an ER-negative breast stem/PC origin, whereas luminal A tumours arise from an ER-positive PC, supporting a hierarchical breast carcinogenesis model, whereas crucial genomic imbalances are clonally selected during the tumour development.
乳腺癌肿瘤是否有共同的细胞起源？不同的乳腺癌分子表型是否源自不同的细胞类型？我们在过去几年中对家族性乳腺肿瘤（BRCA1、BRCA2和非BRCA1/2）进行的研究，将散发性乳腺癌发展的问题扩展到了遗传性乳腺癌。阵列比较基因组杂交（CGH）研究表明，在家族性和散发性乳腺癌亚型中都存在普遍的基因组畸变，这些畸变可能在乳腺肿瘤发展过程中被选择。BRCA1的失活似乎在雌激素受体（ER）阴性的癌症干细胞（CSC）中起关键作用，主要驱动肿瘤发展为基底样表型，在某些情况下发展为腔B型，但也提出了其他致癌事件来解释其余的肿瘤亚型。基底样、ERBB2和腔B型乳腺肿瘤中存在共同的基因组改变，这可能表明这些肿瘤亚型有共同的细胞起源或克隆选择，源自ER阴性的CSC或祖细胞（PC）。最后，ER阳性肿瘤中的特定基因组畸变在细胞暴露于雌激素时可提供细胞增殖优势。我们提出将CSC假说（用于致癌过程）和克隆选择模型（用于肿瘤发展方面）相结合。我们坚持认为，基底样、ERBB2和腔B型散发性和家族性肿瘤亚型起源于ER阴性的乳腺干细胞/祖细胞，而腔A型肿瘤起源于ER阳性的祖细胞，支持一种分级的乳腺癌发生模型，而关键的基因组失衡在肿瘤发展过程中被克隆选择。
