Breast cancers are often blamed on wayward mammary stem cells, but a new study implicates cells lining the mammary ducts as the real perpetrators, at least for a particularly aggressive type of malignancy called basal tumours.

The research was led by Geoffrey Lindeman and Jane Visvader at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia1. They began by studying apparently healthy human breast tissue collected during breast-reduction surgeries. After demonstrating that they could identify distinct subsets of cells, the researchers compared cell types between donors who did and did not have mutations in the BRCA1 gene, which greatly increase the risk of breast cancer. They did not identify differences in behaviour between mature luminal cells or even, as expected, mammary stem cells. Instead, they found that the BRCA1 mutation affects luminal progenitor cells.

Compared to tissue without the mutation, tissue with BRCA1 mutations had a higher percentage of luminal progenitor cells and a lower percentage of mammary stem cells. In culture, luminal progenitor cells carrying the mutation could form colonies even without the addition of a growth factor, known as B27, required by other cells. However, other cell types did not display growth-factor independence even if they did carry the mutation. Finally, the gene-expression pattern of luminal progenitor cells was very similar to that identified in basal breast cancer tumours and in precancerous BRCA1 tissue.

The similarities in gene-expression profiles indicate that basal tumours might generally be sustained by luminal progenitor cells in people with BRCA1 mutations, says Visvader

Max Wicha of the University of Michigan says the research adds new and interesting information to the field, but he suggests another way to consider the data: rather than cancer cells starting from the luminal progenitor stage, they may instead get stuck there2. His lab had previously shown that most breast tissue from people with BRCA1 had normal histology and expressed the estrogen receptor, but the tissue also contained small clumps of cells without the estrogen receptor that also expressed ALDH1, a stem cell marker. These “stem-cell foci” had lost their functioning copy of BRCA1. Further tests in culture and in mice showed that knocking down expression of BRCA1 expanded the population of these cells. In contrast, Visvader's lab studied human tissue with one functioning and one nonfunctioning BRCA1 gene and found an accumulation of luminal progenitor cells.

“Together these data may indicate that the effects of BRCA1 on mammary differentiation may be dose related, with complete loss resulting in arrest at a more primitive state than loss of 50% expression,” says Wicha.

Visvader says she isn't sure how important the dose is. Mouse cells lacking both copies of BRCA1 also show an expanded luminal progenitor cell population with aberrant growth properties.

Ultimately, these results point to more nuanced strategies for fighting basal tumours, says Visvader. “As basal tumors, which include BRCA1-associated tumors, have striking similarities in their gene expression profile to luminal progenitor cells, these progenitor cells may also be important in contributing to growth of the tumor itself.”