Involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ

Abstract

Involution of the mammary gland is an essential process that removes the milk-producing epithelial cells when they become redundant at weaning. It is a two-step process that involves the death of the secretory epithelium and its replacement by adipocytes. During the first phase, remodelling is inhibited and apoptotic cells can be seen in the lumena of the alveoli. In the second phase, apoptosis is accompanied by remodelling of the surrounding stroma and re-differentiation of the adipocytes. Considerable effort has been directed towards understanding the molecular mechanisms of the involution process and this has resulted in the identification of the principal signalling pathways involved.

Figure 1

Signalling events in involution. Milk stasis induces the expression of leukaemia inhibitory factor (LIF) and transforming growth factor (TGF)β3 within 12 hours of forced weaning. These, in turn, phosphorylate and activate the transcription factor Stat3. This results in the induction of apoptosis and shedding of dying cells into the alveolar lumen. Neighbouring cells migrate to close the gap and maintain the integrity of the alveolar structure. Concurrently with these events, members of the death receptor ligand family and their receptors are transcriptionally upregulated and this induces apoptosis through activation of caspase 8. Downstream targets of these pathways are then induced and ensure the transition to the second phase. Following this reversible first phase, matrix metalloproteases (MMP) begin to break down the ECM surrounding each alveolus, resulting in detachment induced apoptosis and collapse of the alveoli. Remodelling is then completed by re-differentiation of the adipoctyes which requires the action of plasmin and MMP3. Full involution returns the gland to a pre-pregnant state. ECM, extracellular matrix.