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. Author manuscript; available in PMC: 2013 Jul 1.
Published in final edited form as: Wiley Interdiscip Rev Dev Biol. 2012 Apr 4;1(4):533–557. doi: 10.1002/wdev.35

Figure 6. Illustration depicting the two stages of mammary gland involution.

Figure 6

Upon weaning, the gland is remodeled back to its pre-pregnancy state. Stage one is reversible and is regulated largely by STAT3, which is induced by leukemia inhibitory factor (LIF) and opposes pro-survival STAT5 signaling by upregulating the expression of numerous proteins including: lysosomal proteases, cathepsins; insulin-like growth factor binding protein5 (IGFBP5); and two regulatory isoforms of phosphatidylinositol 3 kinase, p50alpha (P50A) and p55alpha (P55A). Cell death and limited proteolysis of the extracellular matrix (ECM) occurs during this stage as plasminogen (PLG) is converted to plasmin through the actions of plasma kallikrein (KLK1), yet the alveoli largely retain their shape. This changes during stage two, which is irreversible and characterized by alveolar collapse and adipocyte differentiation. MMPs are released from their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and collaborate with plasmin to return the mammary gland to its pre-lactation state by releasing growth factors (GFs) and remodeling the ECM. For details, see text.