title: The potential prognostic value of connexin 26 and 46 expression in neoadjuvant-treated breast cancer.
abstract: BACKGROUND
  Several classification systems are available to assess pathological response to neoadjuvant chemotherapy in breast cancer, but reliable biomarkers to predict the efficiency of primary systemic therapy (PST) are still missing. Deregulation of gap junction channel forming connexins (Cx) has been implicated in carcinogenesis and tumour progression through loss of cell cycle control. In this study we correlated Cx expression and cell proliferation with disease survival and pathological response to neoadjuvant chemotherapy in breast cancers using existing classification systems.
  
  
  METHODS
  The expression of Cx26, Cx32, Cx43, Cx46 and Ki67 was evaluated in 96 breast cancer patients prior to and after neoadjuvant chemotherapy using duplicate cores in tissue microarrays (TMA). Cx plaques of <1μm were detected with multilayer, multichannel fluorescence digital microscopy. Current classifications to assess residual tumour burden after primary systemic therapy included the EWGBSP, CPS-EG, Miller-Payne, Sataloff and NSABP systems.
  
  
  RESULTS
  In our cohort dominated by hormone receptor (ER/PR) positive and HER2 negative cases, only the CPS-EG classification showed prognostic relevance: cases with scores 1-2 had significantly better overall survival (p=0.015) than cases with scores 3-5. Pre-chemotherapy Cx43 expression correlated positively with hormone receptor status both before and after chemotherapy and had a negative correlation with HER2 expression pre-chemotherapy. There was a positive correlation between Cx32 and HER2 expression pre-chemotherapy and between Cx32 and Ki67 expression post-chemotherapy. A negative correlation was found between post-chemotherapy Cx46 and Ki67 expression. Decreased post-chemotherapy Cx26 expression (<5%) statistically correlated with better overall survival (p=0.011). Moderate or higher Cx46 expression (>20%) pre- and post-chemotherapy correlated with significantly better survival in the intermediate prognostic subgroups of EWGBSP TR2b (p(pre-chemo)=0.006; Sataloff TB (p(pre-chemo)=0.005; p(post-chemo)=0.029) and in Miller-Payne G3 (p(pre-chemo)=0.002; p(post-chemo)=0.012) classifications. Pre-chemotherapy, Cx46 expression was the only marker that correlated with overall survival within these subgroups.
  
  
  CONCLUSIONS
  Our results suggest that Cx46 and Cx26 expression in breast cancer may improve the assessment of pathological response and refine intermediate prognostic subgroups of residual tumour classifications used after neoadjuvant chemotherapy.
authors: 1st Department of Pathology & Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors: Ivett
authors: I
authors: Teleki
authors: Tibor
authors: T
authors: Krenacs
authors: Marcell A
authors: MA
authors: Szasz
authors: Janina
authors: J
authors: Kulka
authors: Barna
authors: B
authors: Wichmann
authors: Cornelia
authors: C
authors: Leo
authors: Barbel
authors: B
authors: Papassotiropoulos
authors: Cosima
authors: C
authors: Riemenschnitter
authors: Holger
authors: H
authors: Moch
authors: Zsuzsanna
authors: Z
authors: Varga
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002277:Carcinoma / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D000072259:Connexin 26; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018365:Neoplasm, Residual; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D000097002:Gap Junction beta-1 Protein
chemical_list: D014408:Biomarkers, Tumor; D000072259:Connexin 26; D018031:Connexin 43; D017630:Connexins; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000097002:Gap Junction beta-1 Protein; C500216:GJA1 protein, human; C000607042:GJB2 protein, human; C082917:GJA3 protein, human; C508053:ERBB2 protein, human
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