Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis

BMC Medicine, Jul 2015

Background Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HR adj  = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HR adj  = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HR adj  = 1.70; 95 % CI = 1.17–2.45). Conclusions ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.

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Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis

Sobral-Leite et al. BMC Medicine Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis Marcelo Sobral-Leite 0 Jelle Wesseling 0 Vincent T. H. B. M. Smit Heli Nevanlinna Martine H. van Miltenburg 0 Joyce Sanders 0 Ingrid Hofland Fiona M. Blows Penny Coulson Gazinska Patrycja Jan H. M. Schellens 0 Rainer Fagerholm Päivi Heikkilä Kristiina Aittomäki Carl Blomqvist Elena Provenzano Hamid Raza Ali Jonine Figueroa Mark Sherman Jolanta Lissowska Arto Mannermaa Vesa Kataja Veli-Matti Kosma Jaana M. Hartikainen Kelly-Anne Phillips kConFab/AOCS Investigators Fergus J. Couch Janet E. Olson Celine Vachon Daniel Visscher Hermann Brenner 2 6 7 Katja Butterbach 2 Volker Arndt 2 Bernd Holleczek 4 Maartje J. Hooning 5 Antoinette Hollestelle 5 John W. M. Martens 5 Carolien H. M. van Deurzen 9 Bob van de Water 10 Annegien Broeks Jenny Chang-Claude 8 Georgia Chenevix-Trench 3 Douglas F. Easton Paul D. P. Pharoah Montserrat García-Closas Marjo de Graauw 10 Marjanka K. Schmidt 0 1 0 Division of Molecular Pathology, Netherlands Cancer Institute , Amsterdam , The Netherlands 1 Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute , Plesmanlaan 121, 1066, CX Amsterdam , The Netherlands 2 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ) , Heidelberg , Germany 3 Department of Genetics, QIMR Berghofer Medical Research Institute , Brisbane , Australia 4 Saarland Cancer Registry , Saarbrücken , Germany 5 Department of Medical Oncology, Erasmus MC Cancer Institute , Rotterdam , The Netherlands 6 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) , Heidelberg , Germany 7 Division of Preventive Oncology, German Cancer Research Center (DKFZ) , Heidelberg , Germany 8 Division of Cancer Epidemiology, Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ) , Heidelberg , Germany 9 Department of Pathology, Erasmus MC Cancer Institute , Rotterdam , The Netherlands 10 Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University , Leiden , The Netherlands Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results: The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45). (Continued on next page) - (Continued from previous page) Conclusions: ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases. Background Breast cancer is a heterogeneous group of pathologic entities with different risk of recurrence and therapy response [1]. In order to improve breast cancer diagnosis and treatment decision, it is necessary to gain a better understanding of the metastatic pathways and etiology. Annexin A1 (ANXA1) protein binds the cellular membrane phospholipids in a Ca2+ regulated manner and can be phosphorylated on several residues both on the N-terminal functional domain and on the C-terminus core [2] by different proteins, such as the epidermal growth factor receptor (EGFR) [3], insulin receptor (IR) [4], TRPM7 channel kinase 1 (ChaK1) [5], protein kinase C (PKC) and protein kinase A (PKA) [6]. ANXA1 has been found in several tissues and regulates physiological mechanisms such as hormone secretion [7], EGFR degradation [8], membrane transport [9], apoptosis [10] and cell differentiation [11]. As a glucocorticoid-induced molecule, ANXA1 plays an impo (...truncated)


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Marcelo Sobral-Leite, Jelle Wesseling, Vincent T H B M Smit, Heli Nevanlinna, Martine H van Miltenburg, Joyce Sanders, Ingrid Hofland, Fiona M Blows, Penny Coulson, Gazinska Patrycja, Jan H M Schellens, Rainer Fagerholm, Päivi Heikkilä, Kristiina Aittomäki, Carl Blomqvist, Elena Provenzano, Hamid Ali, Jonine Figueroa, Mark Sherman, Jolanta Lissowska, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Kelly-Anne Phillips, , Fergus J Couch, Janet E Olson, Celine Vachon, Daniel Visscher, Hermann Brenner, Katja Butterbach, Volker Arndt, Bernd Holleczek, Maartje J Hooning, Antoinette Hollestelle, John W M Martens, Carolien H M van Deurzen, Bob van de Water, Annegien Broeks, Jenny Chang-Claude, Georgia Chenevix-Trench, Douglas F Easton, Paul D P Pharoah, Montserrat García-Closas, Marjo de Graauw, Marjanka K Schmidt. Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis, BMC Medicine, 2015, pp. 156, 13, DOI: 10.1186/s12916-015-0392-6