Estrogen Receptor Levels Lead to Discovery of Third Luminal Cell Population

Estrogen receptor α (ERα), the female sex hormone, is critical in the development and the physiology of the breast; however, these hormones are also involved in breast cancer.

More than 70% of all breast cancers express the ERα and is therefore a common target when creating therapies. One of the most widely used agents, tamoxifen, antagonizes AF-2 and agonizes AF-1, and is used in both primary and secondary breast cancer prevention. A recent study¹sought to learn more about how ER signaling occurs in vivo in normal and cancerous tissue.

The study found that the in vivo role of ERα and its subdomains AF-1 and AF-2 in the mammary epithelium reveal unexpected complexities of this signaling pathway. Prior research believed that there was a dichotomy between ERα+ and ERα- luminal cells, though this study found that based on estrogen receptor (ER) expression levels, a third luminal cell population, the ERα^low cells, can be distinguished.

Researchers were able to determine that different parts of the ER play different roles in the luminal breast cells that give rise to cancer. Depending on whether a cell has low or high levels of the ER, the hormone-depended or the hormone-independent activities were found to be “more or less important” for its function.

Additionally, the study authors also determined that the action of the ER is biphasic; it stimulates both the expansion and growth of breast cells in young mice models but inhibits this expansion during pregnancy.

“This begs the question whether these ER-pseudo-negative breast cells will ultimately turn into estrogen receptor-positive or -negative breast cancers," said Cathrin Brisken, MD, PhD, associate professor of life sciences at the Swiss Federal Institute of Technology Laussane (EPFL).

In terms of underscoring the results in future research, the authors had a few suggestions. “Whether the different ERα states mark distinct cell populations or reflect different transient and/or functional states of otherwise similar luminal cells, will need to be addressed by more in depth single cell sequencing,” they wrote. Furthermore, future studies should look to identify using more sensitive quantitative approaches whether ERα status is 3-part in luminal epithelium, or whether underlying the observations from this study is a continuous, possibly changing gradient in ERα expression levels.

Reference

1. Cagnet S, Ataca D, Sflomos G, et al. Oestrogen receptor α AF-1 and AF-2 domains have cell population-specific functions in the mammary epithelium. Nat Commun. 2018; nature.com/articles/s41467-018-07175-0.pdf. Published November 9, 2018. Accessed November 16, 2018.