Reciprocal Regulation of Annexin A2 and EGFR with Her-2 in Her-2 Negative and Herceptin-Resistant Breast Cancer

Praveenkumar K. Shetty, Sanjay I. Thamake, Swati Biswas, Sonny L. Johansson, Jamboor K. Vishwanatha

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere44299
JournalPloS one
Volume7
Issue number9
DOIs
StatePublished - Sep 5 2012

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Annexin A2
Annexins
Epidermal Growth Factor Receptor
breast neoplasms
Breast Neoplasms
small interfering RNA
Small Interfering RNA
Cell Movement
Cell Survival
Down-Regulation
Chemical activation
Cells
receptors
Triple Negative Breast Neoplasms
Membranes
endocytosis
cell movement
carcinogenesis
Cell proliferation
Receptor Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Shetty, P. K., Thamake, S. I., Biswas, S., Johansson, S. L., & Vishwanatha, J. K. (2012). Reciprocal Regulation of Annexin A2 and EGFR with Her-2 in Her-2 Negative and Herceptin-Resistant Breast Cancer. PloS one, 7(9), [e44299]. https://doi.org/10.1371/journal.pone.0044299

Reciprocal Regulation of Annexin A2 and EGFR with Her-2 in Her-2 Negative and Herceptin-Resistant Breast Cancer. / Shetty, Praveenkumar K.; Thamake, Sanjay I.; Biswas, Swati; Johansson, Sonny L.; Vishwanatha, Jamboor K.

In: PloS one, Vol. 7, No. 9, e44299, 05.09.2012.

Research output: Contribution to journalArticle

Shetty, Praveenkumar K. ; Thamake, Sanjay I. ; Biswas, Swati ; Johansson, Sonny L. ; Vishwanatha, Jamboor K. / Reciprocal Regulation of Annexin A2 and EGFR with Her-2 in Her-2 Negative and Herceptin-Resistant Breast Cancer. In: PloS one. 2012 ; Vol. 7, No. 9.
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