Abstract
The post-lactational regression of mammary gland is a complex multi-step process designed to conserve the biological function of the gland for next pregnancy. This developmental stage is a biological intrigue with great relevance to breast cancer research, and thus has been the subject of intensive scrutiny. Multipronged studies (microarray, proteomics profiling, animal knock-out models) have provided a repertoire of genes critical to involution. However, the caveat of these approaches remains in their failure to reveal post-translational modification(s), an emerging and critical aspect of gene regulation in developmental processes and mammary gland remodeling. The massive surge in the lysosomal enzymes concurrent with the onset of involution has been known for decades, and considered essential for “clearance” purposes. However, functional significance of these enzymes in diverse biological processes distinct from their proteolytic activity is just emerging. Studies from our laboratory had indicated specific post-translational modifications of the aspartyl endopeptidase Cathepsin D (CatD) at distinct stages mammary gland development. This study addresses the biological significance of these modifications in the involution process, and reveals that post-translational modifications drive CatD into the nucleus to cleave Histone 3. The cleavage of Histone 3 has been associated with cellular differentiation and could be critical instigator of involution process. From functional perspective, deregulated expression and increased secretion of CatD are associated with aggressive and metastatic phenotype of breast cancer. Thus unraveling CatD’s physiological functions in mammary gland development will bridge the present gap in understanding its pro-tumorigenic/metastatic functions, and assist in the generation of tailored therapeutic approaches.
Highlights
In adult nulliparous females, the mammary gland is mostly populated by adipocytes with the embedded epithelial network [1], [2]
The involution process occurs in two stages [6]: In the first stage, despite the abundant alveolar cell death there is no remodeling of the glandular structure, this permits the continuance of secretory function if the suckling is resumed
In cultures treated with involution-derived mCatD (ID2, or ID4) features indicative of cell fusion were apparent (Fig. 1E, arrows)
Summary
The mammary gland is mostly populated by adipocytes with the embedded epithelial network [1], [2]. Gestation initiates massive proliferation of the progenitor cells to form lobuloalveolar structures which will differentiate to milk secreting glandular epithelium upon parturition [3,4,5]. The involution process occurs in two stages [6]: In the first stage (reversible, lasting ,48 h), despite the abundant alveolar cell death there is no remodeling of the glandular structure, this permits the continuance of secretory function if the suckling is resumed. In the second phase (non-reversible), the superfluous lobuloalveolar cells, their supporting matrix and accumulated milk are cleared by the combined action of lysosomal enzymes and matrix metalloproteinases, and the gland resumes an almost pre-gestation status [7]. Extensive efforts and multiple approaches including gene expression, proteomic profiles and animal knock-out models have identified genes critical to different stages of mammary gland development [8]. The knock-out models of genes critical for involution [9,10,11,12,13,14,15,16] have revealed delayed involution but none have stopped the process
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