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Published on: July 3, 2025
Latent transforming growth factor binding protein 4 (LTBP4) is downregulated in mouse and human DCIS and mammary
Celine Kretschmer1, Anne Conradi, Wolfgang Kemmner
1Charité Berlin, CVK, Med. Klinik Hepatologie & Gastroenterologie, Augustenburger Platz 1, 13353 Berlin, Germany.
Background:
Transforming growth factor beta (TGF-ß) is able to inhibit the proliferation of epithelial cells and is involved in the carcinogenesis of mammary tumors. Three latent transforming growth factor-ß binding proteins (LTBPs) are known to modulate TGF-ß functions.
Methods:
The current study analyses the expression profiles of LTBP4, its isoforms LTBP1 and LTBP3, and TGF-ß1, TGF-ß2, TGF-ß3, and SMAD2, SMAD3 and SMAD4 in human and murine (WAP-TNP8) DCIS compared to invasive mammary tumors. Additionally mammary malignant (MCF7, Hs578T, MDA-MB361) and non malignant cell lines (Hs578BsT) were analysed. Microarray, q-PCR, immunoblot, immunohistochemistry and immunofluorescence were used.
Results:
In comparison to non-malignant tissues (n = 5), LTBP4 was downregulated in all human and mouse DCIS (n = 9) and invasive mammary adenocarcinomas (n = 5) that were investigated. We also found decreased expression of bone morphogenic protein 4 (BMP4) and increased expression of its inhibitor gremlin (GREM1). Treatment of the mammary tumor cell line (Hs578T) with recombinant TGF-ß1 rescued BMP4 and GREM1 expression.
Conclusion:
We conclude that the lack of LTBP4-mediated targeting in malignant mammary tumor tissues may lead to a possible modification of TGF-ß1 and BMP bioavailability and function.
Insights
Latent transforming growth factor-beta binding protein 4 (LTBP4) is downregulated in mammary tumors, potentially altering transforming growth factor-beta (TGF-ß) and bone morphogenic protein (BMP) functions. This suggests LTBP4
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Transforming growth factor beta (TGF-ß) inhibits epithelial cell proliferation and is implicated in mammary tumor development.
- Latent transforming growth factor-beta binding proteins (LTBPs) are known to regulate TGF-ß activity.
- LTBP4, LTBP1, and LTBP3 are key proteins modulating TGF-ß functions.
Purpose of the Study:
- To analyze the expression profiles of LTBP4, its isoforms (LTBP1, LTBP3), and TGF-ß signaling pathway components (TGF-ß1, TGF-ß2, TGF-ß3, SMAD2, SMAD3, SMAD4) in human and murine mammary tumors.
- To compare gene expression in ductal carcinoma in situ (DCIS) and invasive mammary tumors with non-malignant tissues.
- To investigate the expression of bone morphogenic protein 4 (BMP4) and its inhibitor gremlin (GREM1) in mammary tumors.
Main Methods:
- Gene expression analysis using microarray and quantitative PCR (q-PCR).
- Protein expression analysis via immunoblotting, immunohistochemistry, and immunofluorescence.
- Analysis of human and murine DCIS, invasive mammary tumors, and mammary cell lines.
Main Results:
- LTBP4 expression was significantly downregulated in both human and murine DCIS and invasive mammary adenocarcinomas compared to non-malignant tissues.
- Bone morphogenic protein 4 (BMP4) expression decreased, while its inhibitor gremlin 1 (GREM1) expression increased in malignant tissues.
- Recombinant TGF-ß1 treatment of a mammary tumor cell line restored BMP4 and GREM1 expression.
Conclusions:
- The downregulation of LTBP4 in malignant mammary tissues may alter the bioavailability and function of TGF-ß1 and BMPs.
- LTBP4-mediated targeting appears to be compromised in mammary tumors.
- These findings suggest a potential role for LTBP4 in mammary carcinogenesis and offer insights into TGF-ß and BMP signaling dysregulation.
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