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Carcinogenesis Advance Access originally published online on July 1, 2008
Carcinogenesis 2008 29(8):1475-1482; doi:10.1093/carcin/bgn157
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

An integrative hypothesis about the origin and development of sporadic and familial breast cancer subtypes

Lorenzo Melchor* and Javier Benítez

Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Centre (CNIO), Madrid E-28029, Spain

* To whom correspondence should be addressed. Tel: +34 912246900; Fax: +34 912246923; Email: lmelchor{at}cnio.es

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.

Abbreviations: CGH, comparative genomic hybridisation; CSC, cancer stem cell; ER, oestrogen receptor; IHC, immunohistochemical; LOH, loss of heterozygosity; PC, progenitor cell; SC, stem cell

Received February 11, 2008; revised May 26, 2008; accepted June 28, 2008.


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