Her-2/neu overexpression is associated with thrombospondin-1-related angiogenesis and thrombospondin-1-unrelated lymphangiogenesis in breast cancer

IntroductionHer-2/neu overexpression is linked to poor prognosis and is a significant predictor of the response to trastuzumab (i.e., herceptin) therapy in breast cancer patients. Her-2/neu promotes angiogenesis with thrombospondin-1 (TSP-1) as a mediator in breast cancer development and progression. However, the clinical quantitative evaluation of Her-2/neu and specified localization of TSP-1 are currently lacking.Materials and methodsIn this study, immunohistochemistry was performed to elucidate the in vivo relationships between Her-2/neu and TSP-1 expression, angiogenesis, and lymphangiogenesis in breast cancer. Based on immunohistochemical staining for anti-Her-2/neu and related quantitative scoring of tumor cells, 28 individuals with high Her-2/Neu expression (i.e., with a score of ≥2.0) were recruited into the study group. Another 28 individuals with low Her-2/neu (i.e., with a score of <2.0) were recruited for comparison. These tumors were further stained immunohistochemically for the estrogen receptor (ER), the progesterone receptor (PR), Ki-67, TSP-1, CD31 (an vascular endothelial marker), and D2-40 (a lymphatic endothelial marker).ResultsThe individuals with Her-2/neu overexpression had significantly lower ER and PR expression and a higher Ki-67 index, microvessel count, and lymphatic vessel density in comparison to the individuals with low Her-2/neu expression. High Her-2/neu expression was associated with lower TSP-1 expression in tumor cells (TSP-1/T) and higher TSP-1 expression in the adjacent stroma (TSP-1/S; 17 of 28 individuals). By contrast, low Her-2/neu expression was associated with high TSP-1/T expression and low TSP-1/S (23 of 28 individuals). In one situation, patients with high expression of TSP-1 in tumor cells (a score of >2.0, with 2.0 as the cut-off value) had a significantly lower microvessel density, compared to individuals with low-TSP-1 expression (p = 0.018). However, the lymphatic vessel density was not significantly different from the TSP-1 levels (p = 0.333).ConclusionOur in vivo results showed that Her-2/neu affects the biological manifestations of breast cancer by increasing angiogenesis (which is TSP-1-related) and lymphangiogenesis, which is TSP-1-unrelated).