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Initiation, evolution, phenotype and outcome of BRCA1 and BRCA2 mutation-associated breast cancer

Nature Reviews Cancer volume 12, pages 372–373 (2012)Cite this article

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We 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 et al., in which the authors present the current knowledge of BRCA1 and BRCA2 in genome protection and cancer development. BRCA1 and BRCA2 are known to function in homologous recombination (HR), and they also function in different stages of the DNA damage response. Notably, the functional roles of BRCA1 and BRCA2 are mainly involved in HR, the alteration of which closely relates to DNA damage-associated breast carcinogenesis but which does not explain the formation of specific breast cancer phenotypes in patients with BRCA1 or BRCA2 mutations. BRCA1-mutated cancer tends to be basal-like, and BRCA2-mutated cancer tends to be luminal-like, although mechanistically there is no convincing evidence that BRCA1 mutation induces basal progenitor cancer cells or that BRCA2 mutation corresponds to luminal progenitor cancer cells at the early stages of carcinogenesis2. An important issue, which was not mentioned in the article by Roy et al., is the question of at what time during tumorigenesis do BRCA1 and BRCA2 mutations begin to individually influence breast cancer subtypes.

The authors proposed that hormonally driven growth during each menstrual cycle produces reactive oxygen species (ROS), which cause measurable oxidative DNA damage that is needed for breast carcinogenesis, and which might explain the breast tissue tropism that occurs in women with BRCA1 or BRCA2 mutations. We agree with their speculation that long-term and repeated exposure to ROS, as well as to genotoxic or mutagenic oestrogen metabolites, are important risk factors for breast cancer3. As hormone-associated ROS and oestrogen metabolites are encountered by all normal breast cells regardless of oestrogen receptor (ER) or HER2 status, and as HR is not preferentially activated in different subpopulations of cells in the breast, it seems that BRCA1 and BRCA2 mutations do not contribute to the formation of breast cancer subtypes at the very beginning of cancer initiation. In addition, the facts that the loss of the wild-type allele of BRCA1 or BRCA2 is not required for BRCA1 or BRCA2 mutation-associated breast carcinogenesis4, and that common breast cancer susceptibility alleles are also associated with BRCA1 and BRCA2 mutation-associated tumours5, consistently suggest that BRCA1 and BRCA2 mutations are not the unique determinants of tumour initiation. In other words, it is the overwhelming levels of hormonally driven ROS and the defective capability of HR, rather than BRCA1 or BRCA2 mutation only, that determine the initiation of carcinogenesis. Instead, the phenotype of BRCA1 and BRCA2 mutation-associated breast cancer, which is probably not determined by levels of ROS and HR capability, might gradually form in the process of cancer evolution rather than at cancer initiation.

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  1. Ke-Da Yu and Zhi-Ming Shao are at the Department of Breast Surgery, Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China, and at the Institutes of Biomedical Science, Fudan University, Shanghai 200032, China.,

    Ke-Da Yu & Zhi-Ming Shao

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  1. Ke-Da Yu
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Correspondence to Zhi-Ming Shao.

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Yu, KD., Shao, ZM. Initiation, evolution, phenotype and outcome of BRCA1 and BRCA2 mutation-associated breast cancer. Nat Rev Cancer 12, 372–373 (2012). https://doi.org/10.1038/nrc3181-c1

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