COMMENTARY

Single-Cell Sequencing Upends Assumptions About Breast Cancer Origin

Kathy D. Miller, MD

Disclosures

April 28, 2021

This transcript has been edited for clarity.

This is Dr Kathy Miller from Indiana University. I don't usually discuss basic science research with you, but I saw some results recently from one of my colleagues that were so provocative, I wanted to invite you to think about them with me.

This is work from a group led by my colleague, Dr Hari Nakshatri, which took samples from healthy women who donated normal breast tissue to the Komen Tissue Bank, extracted single cells, and sequenced single-cell gene expression pathways. They then categorized them into clusters using the same technology, the same analytic pathway, that gave us tumor genomic classifications, but using single-cell sequencing rather than whole tumor samples. The researchers then looked at those expression pathways and compared them with the genomic subtypes of tumor cells, looking to understand and begin to propose which normal cells give rise to breast cancer cells.

As a community, we have largely assumed that each different genomic classification arose from a different cell type or a different level of maturity. So perhaps luminal-A breast cancers arose from mature luminal cells and luminal-B breast cancers arose from luminal progenitor cells. And we all assumed that basal-like breast cancers arose from basal epithelial cells. What Dr Nakshatri's group found turns those assumptions on their heads. They found that four normal clusters may give rise to almost all of the breast cancers. Approximately 68% of the breast cancers are most genetically like mature luminal cells. The fourth cell type that seems to give rise to the majority of other breast cancers was a luminal progenitor cell. Of importance, what he found was that different genetic subtypes of breast cancer corresponded with different normal counterparts, and each normal counterpart could be found in different genomic clusters.

This is way more complicated than we had assumed, but this sort of technology, and the ability to do single-cell sequencing in normal and tumor cells, gives us the ability to begin to home in on where breast cancers start. If we can find those cells of origin, we can begin to track those earliest changes. Understanding the earliest changes gives us the real potential to better stratify women's risk and think about much more specific preventive strategies. Now, this is admittedly early days, but it's incredibly exciting to see this sort of work come to the forefront.

Take a look at Hari's work. I think it'll make your head spin. This is Dr Kathy Miller. I'll see you again soon.

Kathy D. Miller, MD, is associate director of clinical research and co-director of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University. Her career has combined both laboratory and clinical research in breast cancer.

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