Abstract
Background: AnnexinA2 (AnxA2) membrane deposition has a critical role in HB-EGF shedding as well as IL-6 secretion in breast cancer cells. This autocrine cycle has a major role in cancer cell proliferation, migration and metastasis. The objective of the study is to demonstrate AnxA2 mediated autocrine regulation via HB-EGF and IL-6 in Her-2 negative breast cancer progression.
Methods: Secretory AnxA2, HB-EGF and IL-6 were analysed in the peripheral blood sample of Her-2 negative (n=20) and positive breast cancer patients (n=16). Simultaneously, tissue expression was analysed by immunohistochemistry. The membrane deposition of these secretory ligands and their autocrine regulation was demonstrated using TNBC cell line model.
Results: AnxA2 and HB-EGF expression are inversely correlated with Her-2, whereas IL-6 expression is seen in both Her-2 negative and positive breast cancer cells. RNA interference studies and up-regulation of AnxA2 proved that AnxA2 is the upstream of this autocrine pathway. Abundant soluble serum AnxA2 is secreted in Her-2 negative breast cancer (359.28±63.73ng/ml) compared to normal (286.10±70.04ng/ml, p?0.01) and Her-2 positive cases (217.75±60.59ng/ml, p?0.0001). In Her-2 negative cases the HB-EGF levels (179.16±118.81pg/ml) was highly significant compared to normal (14.92±17.33pg/ml,p?0.001). IL-6 levels were increased significantly in both the breast cancer phenotypes as compared to normal (p?0.001).
Conclusion: The specific expression pattern of AnxA2 and HB-EGF in TNBC tissues, increased secretion compared to normal cells and their major role in the regulation of EGFR downstream signaling makes these molecules as a potential tissue and serum biomarker and an excellent therapeutic target in Her-2 negative breast cancer.