Elsevier

Developmental Biology

Volume 352, Issue 2, 15 April 2011, Pages 181-190
Developmental Biology

The metastasis-promoting protein S100A4 regulates mammary branching morphogenesis

https://doi.org/10.1016/j.ydbio.2010.12.033Get rights and content
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Abstract

High levels of the S100 calcium binding protein S100A4 also called fibroblast specific protein 1 (FSP1) have been established as an inducer of metastasis and indicator of poor prognosis in breast cancer. The mechanism by which S100A4 leads to increased cancer aggressiveness has yet to be established; moreover, the function of this protein in normal mammary gland biology has not been investigated. To address the role of S100A4 in normal mammary gland, its spatial and temporal expression patterns and possible function in branching morphogenesis were investigated. We show that the protein is expressed mainly in cells of the stromal compartment of adult humans, and during active ductal development, in pregnancy and in involution of mouse mammary gland. In 3D culture models, topical addition of S100A4 induced a significant increase in the TGFα mediated branching phenotype and a concomitant increase in expression of a previously identified branching morphogen, metalloproteinase-3 (MMP-3). These events were found to be dependent on MEK activation. Downregulation of S100A4 using shRNA significantly reduced TGFα induced branching and altered E-cadherin localization. These findings provide evidence that S100A4 is developmentally regulated and that it plays a functional role in mammary gland development, in concert with TGFα by activating MMP-3, and increasing invasion into the fat pad during branching. We suggest that S100A4-mediated effects during branching morphogenesis provide a plausible mechanism for how it may function in breast cancer progression.

Research Highlights

► Expression of S100A4 in breast carcinoma cells is an independent marker of poor prognosis. ► The protein was mainly expressed in the stromal compartment of normal human breast tissue. ► S100A4 increased mammary gland branching phenotype and caused induction of MMP-3 expression. ► S100A4 expression contributed to a proteolytic and invasive phenotype in normal mammary epithelial cells.

Keywords

S100A4
Mammary gland
Branching
MMP-3
TGFα

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