Evidence indicates an increased chance of mammary tumours developing after giving birth and previous studies have shown that the overexpression of Notch3 in mice increases the risk. However, a detailed understanding of Notch3 activity has been lacking. Now, Keli Xu and colleagues employ Notch3β-geo mutant mice to define Notch3 loss-of-function phenotypes in mammary epithelium, using immunohistochemistry, flow cytometry and lineage-tracing experiments. They show that Notch3 deletion reduces the number of luminal or alveolar progenitors during puberty and pregnancy, respectively. Surprisingly, parous mammary glands lacking Notch3 have an excess of parity-identified mammary epithelial cells (PI-MECs), which arise after birth, as well as increased mammary hyperplasia and luminal-like tumours. The researchers transplanted parous Notch3-null PI-MECs into nulliparous (never given birth) or postpartum (just given birth) hosts and found that the transplanted cells only incorporated into postpartum tissue, suggesting that the microenvironment affects PI-MEC activity. Finally, the authors analysed publicly available patient data to show that high levels of Notch3 correlate with relapse-free survival for patients with luminal breast cancer. Although the exact mechanism of Notch3 action needs to be elucidated, these results indicate that Notch3 has a tumour-suppressive function in the parous mammary gland by restricting PI-MEC expansion.
