HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

Abstract

We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin s ) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro-and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

SV40 T/t-common polypeptide inhibits angiogenesis and growth of HER2-overexpressing human ovarian cancer

“…It has been reported that inhibition of HER2 can activate p38 MAPK, which in turn stimulates TSP-1 expression. 9 Because T/t-common can inhibit HER2, we thus tested whether T/t-common could stimulate the activity of p38 MAPK in SK-OV-3 cells. As shown in Figure 5f, compared with mock-or rAd-V-infected SK-OV-3 cells, the level of phospho-p38 was significantly increased in rAd-T/t-infected SK-OV-3 cells, and the level of total p38 protein was not altered in these cells.…”

“…2,7 Preclinical data show that HER2 activation contributes more to the oncogenic phenotype than any of the other HER receptors. 3,8 In fact, overexpression of HER2 has been shown to be correlated with poor prognosis, 4,5 increased angiogenesis, 5,9 enhanced metastatic potential 5,10 and increased chemoresistance of human cancers. 5,11 Angiogenesis is the formation of new blood vessels from existent microvessels and is required for physiological and pathological processes.…”

“…Previous studies has shown that overexpression of HER2 can cause decreased expression of TSP-1 and that inhibition of HER2 with herceptin can activate p38 mitogen-activated protein kinase (p38 MAPK), resulting in increased expression of TSP-1. 9 Ovarian cancer is the leading cause of death from gynecological malignancies among women globally. Despite many efforts that have been made to cure ovarian cancer, long-term survival rates of patients remain low.…”

“…Overexpression of HER2 can result in increased angiogenesis, 9,26 and conversely, inhibition of HER2 can lead to decreased angiogenesis and reduced tumor growth in HER2-overexpressing cancers. 9,27,28 Previously, we reported that SV40 T/t-common polypeptide, which contains the Nterminal common domain of SV40 large T and small t antigens, has transcriptional repression activity 29 and can specifically inhibit HER2 expression in the HER2-overexpressing ovarian carcinoma cells.…”

“…9,27,28 Previously, we reported that SV40 T/t-common polypeptide, which contains the Nterminal common domain of SV40 large T and small t antigens, has transcriptional repression activity 29 and can specifically inhibit HER2 expression in the HER2-overexpressing ovarian carcinoma cells. 30 These results suggest that T/t-common might have the ability to inhibit angiogenesis and tumor growth in HER2-overexpressing ovarian cancer.…”