Key stages in mammary gland development - 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. IntroductionThe mammary gland is a complex, highly specialised tissue that has evolved to provide nutrition for the young. The stunning capacity of the mammary gland to produce milk is matched by the spectacular manner in which the milkproducing epithelial cells are removed when they are no longer required. The mechanism responsible for the destruction of the secretory epithelium is apoptosis, a form of programmed cell death that occurs in all multicellular animals. Since the first description of cell death by Ludwig Gräper in 1914 [1] and the coining of the term apoptosis (Greek for falling leaves) by Kerr, Wyllie and Currie in 1972 [2], the genetics and biochemistry of apoptosis have been extensively studied [3]. It is now apparent that there are variations in the morphological events associated with cell death and these probably reflect distinct molecular mechanisms. To date, 10 genetically programmed cell death pathways have been defined that occur in different situations and in response to diverse stimuli [4]. Cell death is essential during embryonic development for organogenesis and tissue sculpting and to maintain cellular homeostasis in adult organisms. Importantly, while excessive apoptosis can lead to degenerative diseases, insufficient apoptosis can result in cancer. Thus, the study of apoptosis in the mammary gland is important for understanding both the normal biology of post-lactational regression and the events leading to breast tumourigenesis.The physiology and genetics of apoptosis are easily studied in the mouse mammary gland. Most of the secretory epithelium is removed within 6 days of weaning in the mouse and the gland is then remodelled to a pre-pregnant state in preparation for a subsequent pregnancy. The study of apoptosis in the mouse mammary gland has been facilitated by using a forced weaning protocol in which the suckling pups are removed when they are about 10 days old, at the peak of lactation and prior to a natural wean. This precipitates a synchronous involution and allows the study of the molecular mechanism(s) involved and the morphological features associated with these molecular events. Forced involution and glucocorticoid administration studies revealed two phases of involution: a first phase that lasts for 48 hours and is reversible; and a second phase that initiates a remodelling pr...

Physiology of milk secretion

“…At the end of lactation, when regular removal of milk ceases, the MG enters a tissue-remodeling process known as involution [22]. Early after weaning, the epithelial architecture is maintained by the recent exposure to elevated systemic hormones, e.g.…”

PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer

“…Parturition induces full secretory differentiation and milk production. Upon weaning, the secretory cells are eliminated and the gland is remodeled to a duct system that resembles the mature nulliparous state (1). This process of mammary involution involves two sequential rounds of apoptosis.…”

“…PMCA2 overexpression, on the other hand, may play a role in breast cancer progression by conferring resistance to apoptosis. intracellular calcium T he mammary gland undergoes a dramatic cycle of development and regression during reproduction (1). The virgin gland consists of a simple system of epithelial ducts.…”

Nucling, a Novel Apoptosis-associated Protein, Controls Mammary Gland Involution by Regulating NF-κB and STAT3

“…In addition, we previously reported that Nucling mediated apoptosis by suppressing the expression of the anti-apoptotic molecule galectin-3 via NF-B signaling (18). Apoptosis has been identified as a crucial part of involution in the mammary gland (13). However, it currently remains unknown whether Nucling controls apoptosis in mammary gland involution.…”

“…Phagocytosis is a crucial contributor to the remodeling process and removal of cell debris and residual milk in the second phase of involution (12,13). Furthermore, a recent study demonstrated that mammary gland involution was characterized by the recruitment of macrophages with M2 characteristics, which is crucial for epithelial cell death and adipocyte repopulation (14).…”