Abstract:
Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK),
including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal
growth factor receptor (EGFR) and Src which further contributes to oncogenesis in Herceptin resistant and triple negative
breast cancer (TNBC) patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2), a known
substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast
cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast
cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated
downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this
study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling
intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1
cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis,
decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling
complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive
regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.
