The Role of HER3 (erbB3) Overexpression in Peripheral Nerve Sheath Tumors (PNST) as a New Therapeutic Target
Cleofe Romagosa, Cristina Teixido, Angel Garcina, Sara Simonetti, Teresa Moline, Javier Hernandez-Losa, Santiago Ramon y Cajal. Hospital Universitari Vall d'Hebron, Barcelona, Spain; Vall d'Hebron Institut of Oncology, Barcelona, Spain
Background: Malignant peripheral nerve sheath tumors (MPNST) comprise 5-10% of sarcomas. Prognosis is poor and the search for new treatments is ongoing. HER3 is a crucial receptor for neuregulin signalling in Schwann cells but to date, has not been studied in sarcomas. Our aims were to determine the prevalence of HER3 receptor expression in soft tissue tumors, including MPNST, and to evaluate the impact of HER3 inhibition in a subgroup of mesenchymal tumor cell lines.
Design: HER3 expression was evaluated by immunohistochemistry in a total of 50 benign and 71 malignant mesenchymal tumors, including 16 neurofibromas, 16 schwanomas, 14 MPNST and 75 other lesion (uterine and non-uterine leiomiomas and leiomiosarcomas, synovial sarcomas, undifferentiated pleomorphic sarcomas (UPS)). HER3 expression was also evaluated by western blot in 5 different mesenchymal cell lines including RT4 (murine schwann cells) and NF1 (malignant peripheral nerve sheath tumor in NF1 syndrome). Finally, HER3 expression was inhibited by the infection with specific short hairpin RNA (shRNA) in all of them. All the experiments were done by duplicate.
Results: HER3 overexpression was found in 31% of cases. Significantly, HER3 positivity was present in 50% of PNST, 75% of schwanomas, 50% of MPNST and 25% of neurofibromas. In contrast, HER3 positivity was observed in 20% of other mesenchymal tumors. Moreover, HER3 expression was found to be overexpressed in 4 of the 5 cell lines studied and their stable knockdown of HER3 expression induced a decreased of the proliferation rate in all of them and a marked lost of cell viability in the NF1 derived malignant cells.
Conclusions: HER3 overexpression is frequently found in PNST, including 50% of MPNST. Moreover, the in vitro knockdown of HER3 expression clearly has an impact on proliferation rates and viability of mesenchimal tumor cells. These results support the rationale of developing new therapeutic approaches in MPNST based on agents which can block Her3 signaling pathway.
Category: Bone & Soft Tissue
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 20, Tuesday Afternoon