Estrogens are hormones that play central roles in the development and the physiology of the breast, but they are also involved in breast cancer. Like all hormones, estrogens exert their biological effects by binding to dedicated receptors in the target cell

Scientists led by Cathrin Brisken at EPFL have now uncovered that half of the luminal epithelial breast cells that appear to express the estrogen receptor expressed at low levels. Publishing in  Nature Communications, they show that different parts of the estrogen receptor play different roles in the luminal breast cells that give rise to cancer.

Oestrogens, 17β-estradiol (E2) and its metabolites, are pivotal for the development and the physiology of the breast and impinge on breast carcinogenesis. Theis expressed in 40% of the luminal cells that make up the inner layer of the mammary epithelium surrounded by the drives cell proliferation during subsequent estrous cycling and pregnancy. Both hormones rely on paracrine factors to activate stem cells and induces proliferation of other mammary epithelial cells (MECs). 

Estrogen receptors

Depending on whether a cell has low or high levels of the estrogen receptor, the hormone-dependent or the hormone-independent activities are more or less important for its function. Also, the researchers found that the action of the estrogen receptor is biphasic: it stimulates the expansion and growth of breast cells in young mice but inhibits it during pregnancy.

The discovery has immediate implications for the role of ERα in the development of breast cancer. "This begs the question whether these ER-pseudo-negative breast cells will ultimately turn into estrogen receptor -positive or -negative breast cancers," says Cathrin Brisken.

The finding that all ERα signaling is AF-2-dependent provides a molecular basis for the breast-specific efficacy of the widely used breast cancer therapeutic, tamoxifen, which is an AF-2 antagonist but AF-1 agonist.