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Inhibitory activity of YKL-40 in mammary epithelial cell differentiation and polarization induced by lactogenic hormones: a role in mammary tissue involution.

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.

SUBMITTER: Scully S

PROVIDER: S-EPMC3185048 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Inhibitory activity of YKL-40 in mammary epithelial cell differentiation and polarization induced by lactogenic hormones: a role in mammary tissue involution.

Scully Steve S Yan Wei W Bentley Brooke B Cao Qing Jackie QJ Shao Rong R

PloS one 20111003 10

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. ...[more]

PMID: 21991364

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Project description:The development of mammary gland as a lactogenic tissue is a highly coordinated multistep process. The epithelial cells of lactiferous tubules undergo profound changes during the developmental window of puberty, pregnancy, and lactation. Several hormones including estrogen, progesterone, glucocorticoids and prolactin act in concert, and orchestrate the development of mammary gland. Understanding the gene regulatory networks that coordinate proliferation and differentiation of HC11 Mammary Epithelial stem-like Cells (MEC) under the influence of lactogenic hormones is critical for elucidating the mechanism of lactogenesis in detail. In this study, we analyzed transcriptome profiles of undifferentiated MEC (normal) and compared them with Murine Embryonic Stem Cells (ESC) using next-generation mRNA sequencing. Further, we analyzed the transcriptome output during lactogenic differentiation of MEC following treatment with glucocorticoids (primed state) and both glucocorticoids and prolactin together (prolactin state). We established stage-specific gene regulatory networks in ESC and MEC (normal, priming and prolactin states). We validated the top up-and downregulated genes in each stage of differentiation of MEC by RT-PCR and found that they are comparable with that of RNA-seq data. HC11 MEC display decreased expression of Pou5f1 and Sox2, which is crucial for the differentiation of MEC, which otherwise ensure pluripotency to ESC. Cited4 is induced during priming and is involved in milk secretion. MEC upon exposure to both glucocorticoids and prolactin undergo terminal differentiation, which is associated with the expression of several genes, including Xbp1 and Cbp that are required for cell growth and differentiation. Our study also identified differential expression of transcription factors and epigenetic regulators in each stage of lactogenic differentiation. We also analyzed the transcriptome data for the pathways that are selectively activated during lactogenic differentiation. Further, we found that selective expression of chromatin modulators (Dnmt3l, Chd9) in response to glucocorticoids suggests a highly coordinated stage-specific lactogenic differentiation of MEC.

Dataset Information

Inhibitory activity of YKL-40 in mammary epithelial cell differentiation and polarization induced by lactogenic hormones: a role in mammary tissue involution.

Publications

Inhibitory activity of YKL-40 in mammary epithelial cell differentiation and polarization induced by lactogenic hormones: a role in mammary tissue involution.

Similar Datasets

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