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BRCA1 and BRCA2: a common pathway of genome protection but different breast cancer subtypes

Nature Reviews Cancer volume 12, page 372 (2012)Cite this article

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I read with great interest the recent Opinion article (BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nature Rev. Cancer 12, 68–78 (2012))1 by Roy and colleagues. Both BRCA1 and BRCA2 have vital roles in the same DNA repair pathway, homologous recombination (HR); nevertheless, the pathology and molecular biology of breast tumours that develop in BRCA1-mutation carriers are very different from those of BRCA2 mutation-associated breast tumours. Roy and colleagues provide several interesting theories to explain why BRCA1-mutation carriers predominantly develop oestrogen receptor (ER)-negative tumours, whereas BRCA2-mutation carriers show the same range of molecular subtypes as sporadic breast cancer. In this correspondence, I discuss a plausible explanation for this phenomenon, the cell of origin, based on recent findings.

Mammary stem cells (MaSCs), from which all the mammary epithelial cells originate, are ER-negative and give rise to progenitor cells2. Besides its roles in HR and many other processes, BRCA1 is required for the differentiation of progenitor cells to mature ER-positive luminal cells, whereas BRCA2 is not3. Consequently, luminal progenitor cells may accumulate in BRCA1-mutation carriers when the wild-type allele is lost, as they are unable to differentiate4. Having a defective HR pathway and the ability to self-renew, these cells are candidates to develop into undifferentiated ER-negative breast cancer5. Thus, because a lack of BRCA1 prevents cell differentiation, it can be assumed that most of the breast tumours that develop in BRCA1-mutation carriers originate from the same cell lineage, making BRCA1-associated cancer a homogeneous tumour group. Conversely, BRCA2-associated breast cancer is a heterogeneous group, showing the same diversity in molecular subtypes as sporadic breast cancer, with similar pathological and molecular characteristics6,7; this suggests that its origin is derived from different cell lineages. The average age at which BRCA2-mutation carriers are diagnosed with breast cancer is later than BRCA1 carriers; additionally, the risk of BRCA2-mutation carriers developing breast cancer is significantly lower. This supports the idea that BRCA1-deficient cells have an early advantage in becoming a tumour cell compared with BRCA2-deficient cells; that is, they have the ability to self-renew.

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References

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  1. Simon A. Joosse is at the Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. s.joosse@in-silico.net,

    Simon A. Joosse

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S.A.J. is a named contributor on the patent for the array-CGH classifier referred to in this correspondence.

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Joosse, S. BRCA1 and BRCA2: a common pathway of genome protection but different breast cancer subtypes. Nat Rev Cancer 12, 372 (2012). https://doi.org/10.1038/nrc3181-c2

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