title: Cyclooxygenase-2 (COX2) and p53 protein expression are interdependent in breast cancer but not associated with clinico-pathological surrogate subtypes, tumor aggressiveness and patient survival.
abstract: In the last decade, different molecular subtypes of breast cancer have been proposed. Although displaying appreciable association with disease prognosis and the prognostic value of cytotoxic and endocrine therapeutic modalities, the subtypes seem to fail at completely explaining disease behavior and response to treatment. Molecules such as those of the cyclocooxigenase (COX) family, currently composed of three entities (COX 1, 2 and 3) have been shown to be associated with breast carcinogenesis, and the analysis of p53 expression in breast tumors may also offer some additional prognostic clues. Our study is aimed at assessing COX2 and p53 expression in these clinico-pathological surrogate subtypes, and to evaluate whether the expression of these molecules can help further explain the variability in prognosis still found within the clinico-pathological subtypes groups of breast cancer.
  
  
  METHODS
  A total of 183 breast cancer samples were obtained from women treated at the Womeńs Hospital of Campinas State University, Campinas, Brazil, between June 2008 and January 2011. Immunohistochemistry was performed to detect the expression of ER, PR, ki67, COX2, and p53 and the HER2 status of the 183 specimens was assessed using FISH. Two COX2 staining thresholds were used to define COX2 positivity: low threshold (LT): moderate and intense staining were considered positive; high-threshold (HT): only intense staining was considered positive.
  
  
  RESULTS
  There was no trend in COX2 overexpression from Luminal A-like to Triple-negative subtypes. By contrast, p53 was expressed in roughly 67% of the Luminal A-like tumors, 50% of the Luminal B-like HER2 positive tumors, 60.9% of the Luminal B-like HER2 negative, approximately 82% of the HER2 positive (non-luminal) and 87% of the Triple-negative tumors (p for trends=0.06). There was a significantly higher proportion of COX2 positive (LT) tumors (66.9%) when p53 was also positive compared to when the tumor was negative for p53 (in which case only18.0% of the tumors were positive for COX2; p<0.001). Neither marker was found to be associated with patients' survival.
  
  
  CONCLUSIONS
  There seems to be a positive association between the expressions of COX2 and p53. Otherwise, neither the expression of COX nor that of p53 was associated with clinico-pathological subtypes, tumor features and prognosis. It seems to be too early to elect the detection of COX2 using IHC as prognostic or predictive tool, but incipient evidence points toward a possible role for the marker.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences PO Box 6111, State University of Campinas-UNICAMP, Campinas, SP, Brazil. Electronic address: katiapserra@gmail.com.
authors.forename: Katia Piton
authors.initials: KP
authors.lastname: Serra
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences PO Box 6111, State University of Campinas-UNICAMP, Campinas, SP, Brazil.
authors.forename: Raquel Mary Rodrigues
authors.initials: RM
authors.lastname: Peres
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences PO Box 6111, State University of Campinas-UNICAMP, Campinas, SP, Brazil. Electronic address: luis.sarian@gmail.com.
authors.forename: Luis Otávio
authors.initials: LO
authors.lastname: Sarian
authors.affiliation: Department of Pathology, Street Tessalia Vieira de Camargo, 126, State University of Campinas-UNICAMP, Postal Code 13083-887, Campinas, São Paulo, Brazil; Department of Pathology, A.C. Camargo Cancer Hospital, Antônio Prudente Foundation, Street Professor Antônio Prudente,109, Liberdade, 01509-900 São Paulo, São Paulo, Brazil. Electronic address: vassallomeister@gmail.com.
authors.forename: José
authors.initials: J
authors.lastname: Vassallo
authors.affiliation: Department of Pathology, Street Tessalia Vieira de Camargo, 126, State University of Campinas-UNICAMP, Postal Code 13083-887, Campinas, São Paulo, Brazil. Electronic address: pinto.glauceaparecida@gmail.com.
authors.forename: Glauce Aparecida
authors.initials: GA
authors.lastname: Pinto
authors.affiliation: Department of Pathology, Street Tessalia Vieira de Camargo, 126, State University of Campinas-UNICAMP, Postal Code 13083-887, Campinas, São Paulo, Brazil. Electronic address: geisi.paiva@gmail.com.
authors.forename: Geisilene Russano de Paiva
authors.initials: GR
authors.lastname: Silva
authors.affiliation: Department of Pathology, A.C. Camargo Cancer Hospital, Antônio Prudente Foundation, Street Professor Antônio Prudente,109, Liberdade, 01509-900 São Paulo, São Paulo, Brazil. Electronic address: fasoares@hcancer.org.br.
authors.forename: Fernando Augusto
authors.initials: FA
authors.lastname: Soares
authors.affiliation: Department of Pathology, A.C. Camargo Cancer Hospital, Antônio Prudente Foundation, Street Professor Antônio Prudente,109, Liberdade, 01509-900 São Paulo, São Paulo, Brazil. Electronic address: iwcunha@hcancer.org.br.
authors.forename: Isabela Werneck
authors.initials: IW
authors.lastname: da Cunha
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences PO Box 6111, State University of Campinas-UNICAMP, Campinas, SP, Brazil. Electronic address: ju_espinola@yahoo.com.
authors.forename: Juliana
authors.initials: J
authors.lastname: Espinola
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences PO Box 6111, State University of Campinas-UNICAMP, Campinas, SP, Brazil. Electronic address: adrianomb@hotmail.com.
authors.forename: Adriano Mesquita
authors.initials: AM
authors.lastname: Bento
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences PO Box 6111, State University of Campinas-UNICAMP, Campinas, SP, Brazil. Electronic address: leticiamdc@gmail.com.
authors.forename: Leticia Marinho
authors.initials: LM
authors.lastname: Del Corso
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medical Sciences PO Box 6111, State University of Campinas-UNICAMP, Campinas, SP, Brazil. Electronic address: sophie.derchain@gmail.com.
authors.forename: Sophie
authors.initials: S
authors.lastname: Derchain
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: Breast cancer; COX2; Clinico-pathological surrogate subtypes; Saint Gallen; p53