# Trastuzumab Decreases the Expression of G1/S Regulators and Syndecan-4 Proteoglycan in Human Rhabdomyosarcoma

## TL;DR

This study shows that trastuzumab, a drug targeting HER2, reduces key regulators of cell cycle and SDC4 in rhabdomyosarcoma, a type of childhood cancer.

## Contribution

The study reveals that trastuzumab affects SDC4 and cell cycle regulators in rhabdomyosarcoma, suggesting potential therapeutic benefits.

## Key findings

- Trastuzumab reduces SDC4 expression and G1/S regulators like cyclin E and D1 in rhabdomyosarcoma cells.
- Trastuzumab also lowers MyoD levels, a key factor for RMS cell survival.
- HER2 expression in about half of RMS cases suggests trastuzumab could have therapeutic value.

## Abstract

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, arises from skeletal muscle cells that fail to differentiate terminally. Two subgroups of RMS, fusion-positive and fusion-negative RMS (FPRMS and FNRMS, respectively), are characterized by the presence or absence of the PAX3/7-FOXO1 fusion gene. RMSs frequently exhibit increased expression of human epidermal growth factor receptor-2 (HER2). Trastuzumab is a humanized monoclonal antibody targeting HER2, and its potential role in RMS treatment remains to be elucidated. Syndecan-4 (SDC4) is a heparan sulfate proteoglycan (HSPG) affecting myogenesis via Rac1-mediated actin remodeling. Previously, we demonstrated that the SDC4 gene is amplified in 28% of human FNRMS samples, associated with high mRNA expression, suggesting a tumor driver role. In this study, after analyzing the copy numbers and mRNA expressions of other HSPGs in human RMS samples, we found that in addition to SDC4, syndecan-1, syndecan-2, and glypican-1 were also amplified and highly expressed in FNRMS. In RD (human FNRMS) cells, elevated SDC4 expression was accompanied by low levels of phospho-Ser179 of SDC4, leading to high Rac1-GTP activity. Notably, this high SDC4 expression in RD cells decreased following trastuzumab treatment. Trastuzumab decreased the levels of G1/S checkpoint regulators cyclin E and cyclin D1 and reduced the cell number; however, it also downregulated the cyclin-dependent kinase inhibitor p21. The level of MyoD, a transcription factor essential for RMS cell survival, also decreased following trastuzumab administration. Our findings contribute to the understanding of the role of SDC4 in FNRMS. Since HER2 is expressed in about half of RMSs, the trastuzumab-mediated changes observed here may have therapeutic implications.