Abstract
The postnatal mammary gland undergoes repeated cycles of proliferation and cell death, most notably when the fully differentiated (lactating) gland dedifferentiates to a prelactation state. Accumulation of milk proteins in the secretory epithelium creates the stress signal that triggers this process (involution). How this stress is perceived, and the cellular processes that are subsequently activated, remain unclear. We now report that Unfolded Protein Response (UPR), autophagy, and apoptosis related genes cluster separately during lactation and involution in the mouse mammary gland. Time-course experiments in rodents show that autophagy and UPR signaling are tightly co-regulated at the transition from reversible to irreversible involution. Inhibition of autophagy by chloroquine or genetic deletion of one ATG7 allele enhanced progression of mammary involution into the irreversible phase, as characterized by an early/precocious induction of apoptosis. These are the first preclinical in vivo data in support of a clinical trial testing an autophagy inhibitor for prevention of intraductal breast malignancy progression to invasive breast cancer. In marked contrast, stimulation of autophagy by low dose tunicamycin treatment reduced apoptosis and extended the reversible phase of involution by sustaining the secretory epithelium. Autophagy stimulators could be used short-term to promote lactation in women experiencing difficulties or irregularities in nursing. Taken together, these data indicate that UPR and autophagy play a key role in regulating the balance between cell survival and apoptosis during normal mammary gland regression.
Highlights
The mammary gland is a unique tissue in its ability to undergo repeated cycles of cell proliferation, differentiation, death, and tissue remodeling during and after puberty, and during the process of involution that occurs after cessation of lactation
Principal component analysis (PCA) revealed separation of different time points in involution process To study the expression of Unfolded Protein Response (UPR), autophagy, and apoptosis genes in the mammary gland, first we searched published gene expression microarray datasets obtained at different stages of mammary development; only studies containing involution with several data points were selected[21,22] and analyzed as presented in Materials and methods
We assigned these genes to different groups based on their pathway membership as annotated in Gene Ontology (GO; Autophagy Gene Ontology GO:0006914, Apoptosis Process GO:0006915 and Response to unfolded protein GO:0006986; Table 1; Supplementary Table S2)
Summary
The mammary gland is a unique tissue in its ability to undergo repeated cycles of cell proliferation, differentiation, death, and tissue remodeling during and after puberty, and during the process of involution that occurs after cessation of lactation. Wärri et al Cell Death Discovery (2018)4:40 systemic hormones and is irreversible; tissue architecture is destroyed and a robust remodeling is accompanied by adipogenesis[8]. Apoptosis occurs during both phases, triggered by detachment of luminal epithelial cells from the basement membrane[9]. In Beclin (Becn)[1] null mouse embryos, widespread cell death occurs and is embryonic lethal[14], suggesting a prosurvival role for autophagy during early development. Increased Becn[1] expression has been described at the end of lactation in the adult mammary gland and interpreted to imply a cellular prodeath role[12]. Autophagy may exhibit either a prosurvival[9,15] or prodeath function[16]
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