Abstract
We previously reported that a secreted glycoprotein YKL-40 acts as an angiogenic factor to promote breast cancer angiogenesis. However, its functional role in normal mammary gland development is poorly understood. Here we investigated its biophysiological activity in mammary epithelial development and mammary tissue morphogenesis. YKL-40 was expressed exclusively by ductal epithelial cells of parous and non-parous mammary tissue, but was dramatically up-regulated at the beginning of involution. To mimic ductal development and explore activity of elevated YKL-40 during mammary tissue regression in vivo, we grew a mammary epithelial cell line 76N MECs in a 3-D Matrigel system in the presence of lactogenic hormones including prolactin, hydrocortisone, and insulin. Treatment of 76N MECs with recombinant YKL-40 significantly inhibited acinar formation, luminal polarization, and secretion. YKL-40 also suppressed expression of E-cadherin but increased MMP-9 and cell motility, the crucial mechanisms that mediate mammary tissue remodeling during involution. In addition, engineering of 76N MECs with YKL-40 gene to express ectopic YKL-40 recapitulated the same activities as recombinant YKL-40 in the inhibition of cell differentiation. These results suggest that YKL-40-mediated inhibition of cell differentiation and polarization in the presence of lactogenic hormones may represent its important function during mammary tissue involution. Identification of this biophysiological property will enhance our understanding of its pathologic role in the later stage of breast cancer that is developed from poorly differentiated and highly invasive cells.
Highlights
Mammary gland development during childhood does little more than keep pace with the general growth of the body until puberty
Hematoxylin and eosin (H & E) analysis revealed that a few mammary ducts were scattered in fat-rich stroma from both virgin mice and parous mice, whereas extensive secreted ducts were observed in the tissue from early involution (Figure 1a-c)
An epithelial surface marker E-cadherin (E-cad) responsible for cellcell adhesion was significantly decreased during and after weaning compared with the ducts from virgin mice (Figure 1m-o). These data suggest that ductal epithelial property is lost during involution and this physiological change may be associated with elevated expression of YKL-40
Summary
Mammary gland development during childhood does little more than keep pace with the general growth of the body until puberty. It is well established that proper organization, maintenance, and function of the mammary ducts are largely ascribed to cell-cell adhesion and polarization of ductal epithelium and its interaction with extracellular matrix (ECM) [4]. These epithelial cells coordinate together to generate and maintain a polarized cellular layer that is surrounded by myoepithelial cells and ECM, contrary to inner acinar cells that lack attachment to ECM and rapidly undergo apoptosis, a death program analogous to anoikis [5,6]. The ECM-rich basement membrane is able to interact with epithelial cells through binding different integrins accumulated at the abluminal membrane and to induce activation of FAK, PI3K, and Bcl; enhancing the epical-basal polarization and survival of epithelial cells [7,8]
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