title: Annexin A2 and its downstream IL-6 and HB-EGF as secretory biomarkers in the differential diagnosis of Her-2 negative breast cancer.
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 annexinA2-mediated autocrine regulation via HB-EGF and IL-6 in Her-2 negative breast cancer progression. Methods Secretory annexinA2, 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 triple-negative breast cancer cell line model. Results Annexina2 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 upregulation of annexinA2 proved that annexinA2 is the upstream of this autocrine pathway. Abundant soluble serum annexinA2 is secreted in Her-2 negative breast cancer (359.28 ± 63.73 ng/mL) compared with normal (286.10 ± 70.04 ng/mL, P < 0.01) and Her-2 positive cases (217.75 ± 60.59 ng/mL, P < 0.0001). In Her-2 negative cases, the HB-EGF concentrations (179.16 ± 118.81 pg/mL) were highly significant compared with normal (14.92 ± 17.33 pg/mL, P < 0.001). IL-6 concentrations were increased significantly in both the breast cancer phenotypes as compared with normal ( P < 0.001). Conclusion The specific expression pattern of annexinA2 and HB-EGF in triple-negative breast cancer tissues, increased secretion compared with normal cells, and their major role in the regulation of EGFR downstream signalling makes these molecules as a potential tissue and serum biomarker and an excellent therapeutic target in Her-2 negative breast cancer.
authors: 1 Central Research Laboratory/Department of Biochemistry, SDM College of Medical Sciences & Hospital, Dharwad, India.
authors: Praveenkumar
authors: P
authors: Shetty
authors: 1 Central Research Laboratory/Department of Biochemistry, SDM College of Medical Sciences & Hospital, Dharwad, India.
authors: Vidya S
authors: VS
authors: Patil
authors: 2 Department of Surgery, SDM College of Medical Sciences & Hospital, Dharwad, India.
authors: Rajashekar
authors: R
authors: Mohan
authors: 1 Central Research Laboratory/Department of Biochemistry, SDM College of Medical Sciences & Hospital, Dharwad, India.
authors: Leonard Clinton
authors: LC
authors: D'souza
authors: 1 Central Research Laboratory/Department of Biochemistry, SDM College of Medical Sciences & Hospital, Dharwad, India.
authors: Anil
authors: A
authors: Bargale
authors: 3 Karnataka Cancer Therapy and Research Institute, Hubli, India.
authors: Basavaraj R
authors: BR
authors: Patil
authors: 4 Department of Pathology, SDM College of Medical Sciences & Hospital, Dharwad, India.
authors: U S
authors: US
authors: Dinesh
authors: 5 Department of Medicine, SDM College of Medical Sciences & Hospital, Dharwad, India.
authors: Vikram
authors: V
authors: Haridas
authors: 1 Central Research Laboratory/Department of Biochemistry, SDM College of Medical Sciences & Hospital, Dharwad, India.
authors: Shrirang P
authors: SP
authors: Kulkarni
mesh_terms: D000328:Adult; D017306:Annexin A2 / Q000097:blood / Q000235:genetics*; D019898:Autocrine Communication; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D001943:Breast Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003937:Diagnosis, Differential; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D066257:Heparin-binding EGF-like Growth Factor / Q000097:blood / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D017306:Annexin A2; D014408:Biomarkers, Tumor; D066257:Heparin-binding EGF-like Growth Factor; D015850:Interleukin-6; D018719:Erb-b2 Receptor Tyrosine Kinases; C587883:HBEGF protein, human; C508600:IL6 protein, human; C508053:ERBB2 protein, human
keywords: AnxA2; Her-2; TNBC; Tumour markers; immunoassay; receptor ligands