Abstract Aim Triple-negative breast cancer (TNBC) is a group of tumors that do not express HER2, estrogen and progesterone receptors. Due to reduced response to conventional antitumor therapies and poor prognosis, new targeted agents are needed for such aggressive sub-type of breast cancer. Multiple lines of evidence support the idea that deregulation of Hedgehog (Hh) signaling has a role in the pathogenesis of breast cancer, in part through the promotion of epithelial-stromal interactions. Therefore, the inhibition of the Hh pathway has been proposed as an interesting therapeutic approach Methods The main objective of this study is to investigate the role of Hh signaling pathway in TNBC. To this aim, we used a panel of human breast cancer cell lines, including five cancer cells lines positive for ER, PR and HER2 expression (nTNBC) and five Triple Negative Breast Cancer cell lines (TNBC). The effects induced by the Smo-inhibitor NVP-LDE225 on proliferation, angiogenesis and signal transduction of breast cancer cells were investigated Results GLI1, one of the major transcription factors induced by Hh signaling activation, is more expressed in TNBC than in nTNBC cell lines. Consistently, NVP-LDE225 treatment induced a more pronounced inhibitory effect on TNBC, in terms of tumor growth: while nTNBC cells display an IC50 of∼5mM, TNBC cell lines are more sensitive, with an average IC50 of∼2mM. In addition, Hh inhibition caused a robust impairment of TNBC cells invasion capabilities. These effects are coupled with a strong inhibition of VEGFA production by both tumor and stromal cells (human fibroblasts and HUVECs). Accordingly, NVP-LDE225 treatment interfered with HUVEC capillary tube formation, an effect even more evident than that observed with bevacizumab, the only targeted agent approved to date for TNBC patients Conclusions Our results suggest that Hh has a specific role in breast epithelial-stromal interactions by regulation of angiogenesis. An orthotopic in vivo experiment in nude mice xenografted with TNBC cells, testing the combination of NVP-LDE225 with bevacizumab, is ongoing Disclosure All authors have declared no conflicts of interest.

1599P - Effects of Hedgehog signaling inhibition on epithelial-stromal interactions in triple negative breast cancer cells

A. Servetto;L. Formisano;VENEZIANI, BIANCA MARIA;DE PLACIDO, SABINO;BIANCO, ROBERTO
2014

Abstract

Abstract Aim Triple-negative breast cancer (TNBC) is a group of tumors that do not express HER2, estrogen and progesterone receptors. Due to reduced response to conventional antitumor therapies and poor prognosis, new targeted agents are needed for such aggressive sub-type of breast cancer. Multiple lines of evidence support the idea that deregulation of Hedgehog (Hh) signaling has a role in the pathogenesis of breast cancer, in part through the promotion of epithelial-stromal interactions. Therefore, the inhibition of the Hh pathway has been proposed as an interesting therapeutic approach Methods The main objective of this study is to investigate the role of Hh signaling pathway in TNBC. To this aim, we used a panel of human breast cancer cell lines, including five cancer cells lines positive for ER, PR and HER2 expression (nTNBC) and five Triple Negative Breast Cancer cell lines (TNBC). The effects induced by the Smo-inhibitor NVP-LDE225 on proliferation, angiogenesis and signal transduction of breast cancer cells were investigated Results GLI1, one of the major transcription factors induced by Hh signaling activation, is more expressed in TNBC than in nTNBC cell lines. Consistently, NVP-LDE225 treatment induced a more pronounced inhibitory effect on TNBC, in terms of tumor growth: while nTNBC cells display an IC50 of∼5mM, TNBC cell lines are more sensitive, with an average IC50 of∼2mM. In addition, Hh inhibition caused a robust impairment of TNBC cells invasion capabilities. These effects are coupled with a strong inhibition of VEGFA production by both tumor and stromal cells (human fibroblasts and HUVECs). Accordingly, NVP-LDE225 treatment interfered with HUVEC capillary tube formation, an effect even more evident than that observed with bevacizumab, the only targeted agent approved to date for TNBC patients Conclusions Our results suggest that Hh has a specific role in breast epithelial-stromal interactions by regulation of angiogenesis. An orthotopic in vivo experiment in nude mice xenografted with TNBC cells, testing the combination of NVP-LDE225 with bevacizumab, is ongoing Disclosure All authors have declared no conflicts of interest.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11588/598749
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