Molecular mechanism of mammary gland involution: An update

The mammary gland (MG) is a unique organ responsible for milk synthesis, secretion, and involution to prepare the gland for subsequent lactation. The mammary epithelial cells (MECs), which are the milk synthesizing units of the MG, proliferate, differentiate, undergo apoptosis and regenerate following a cyclic pathway of lactation - involution - lactation, fine-tuning these molecular events through hormones, growth factors and other regulatory molecules. The developmental stages of the MG are embryonic, prepubertal, pubertal, pregnancy, lactation and involution, with major developmental processes occurring after puberty. The involution stage includes interesting physiological processes such as MEC apoptosis, matrix remodeling, and the generation of cells regaining the shape of a virgin MG. Signal transducer and activator of transcription 3 (STAT3) is the established master regulator of this process and aberrant expression of STAT3 leads to subnormal involution and may induce neoplasia. Several studies have reported on the molecular mechanism of MG involution with substantial knowledge being gained about this process; however, a deep understanding of this phenomenon has yet to be attained. This review focuses deeply on the molecular details of post-lactational regression, the signaling pathways involved in the lactation-involution cycle, and the latest developments in STAT3-associated MG neoplasia. Deep insight into the involution process will pave the way towards understanding the biology, apoptosis, and oncogenesis of the MG.