Alveolar cells in the mammary gland: lineage commitment and cell death

The mammary gland provides a spectacular example of physiological cell death whereby the cells that produce milk during lactation are removed swiftly, efficiently, and without inducing inflammation upon the cessation of lactation. The milk-producing cells arise primarily during pregnancy and comprise the alveolar lineage that is specified by signalling pathways and factors that are activated in response to pregnancy hormones. There are at least two alveolar sub-lineages, one of which is marked by the presence of binucleate cells that are especially susceptible to programmed cell death during involution. This process of post-lactational regression, or involution, is carefully orchestrated and occurs in two phases, the first results in a rapid switch in cell fate with the secretory epithelial cells becoming phagocytes whereupon they destroy dead and dying cells from milk. This reversible phase is followed by the second phase that is marked by an influx of immune cells and a remodelling of the gland to replace the alveolar cells with re-differentiated adipocytes, resulting in a return to the pre-pregnant state in preparation for any subsequent pregnancies. The mouse mammary gland provides an excellent experimental tool with which to investigate lineage commitment and the mechanisms of programmed cell death that occur in a normal physiological process. Importantly, involution has highlighted a role for lysoptosis, a mechanism of cell death that is mediated by lysosomal cathepsins and their endogenous inhibitors, serpins. In this review, I discuss alveolar lineage commitment during pregnancy and the programmed cell death pathways that destroy these cells during involution.