Correlations of differentially expressed gap junction connexins Cx26, Cx30, Cx32, Cx43 and Cx46 with breast cancer progression and prognosis.
OBJECTIVE
Connexins and their cell membrane channels contribute to the control of cell proliferation and compartmental functions in breast glands and their deregulation is linked to breast carcinogenesis. Our aim was to correlate connexin expression with tumor progression and prognosis in primary breast cancers.


METHODS
Meta-analysis of connexin isotype expression data of 1809 and 1899 breast cancers from the Affymetrix and Illumina array platforms, respectively, was performed. Expressed connexins were also monitored at the protein level in tissue microarrays of 127 patients equally representing all tumor grades, using immunofluorescence and multilayer, multichannel digital microscopy. Prognostic correlations were plotted in Kaplan-Meier curves and tested using the log-rank test and cox-regression analysis in univariate and multivariate models.


RESULTS
The expression of GJA1/Cx43, GJA3/Cx46 and GJB2/Cx26 and, for the first time, GJA6/Cx30 and GJB1/Cx32 was revealed both in normal human mammary glands and breast carcinomas. Within their subfamilies these connexins can form homo- and heterocellular epithelial channels. In cancer, the array datasets cross-validated each other's prognostic results. In line with the significant correlations found at mRNA level, elevated Cx43 protein levels were linked with significantly improved breast cancer outcome, offering Cx43 protein detection as an independent prognostic marker stronger than vascular invasion or necrosis. As a contrary, elevated Cx30 mRNA and protein levels were associated with a reduced disease outcome offering Cx30 protein detection as an independent prognostic marker outperforming mitotic index and necrosis. Elevated versus low Cx43 protein levels allowed the stratification of grade 2 tumors into good and poor relapse free survival subgroups, respectively. Also, elevated versus low Cx30 levels stratified grade 3 patients into poor and good overall survival subgroups, respectively.


CONCLUSIONS
Differential expression of Cx43 and Cx30 may serve as potential positive and negative prognostic markers, respectively, for a clinically relevant stratification of breast cancers.
1st Department of Pathology & Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Ivett
I
Teleki
2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Attila Marcell
AM
Szasz
1st Department of Pathology & Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Mate Elod
ME
Maros
MTA TTK Lendulet Cancer Biomarker Research Group, Budapest, Hungary; 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary; MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary.
Balazs
B
Gyorffy
2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
Janina
J
Kulka
1st Department of Pathology & Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Nora
N
Meggyeshazi
1st Department of Pathology & Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Gergo
G
Kiszner
1st Department of Pathology & Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Peter
P
Balla
1st Department of Pathology & Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Aliz
A
Samu
1st Department of Pathology & Experimental Cancer Research, Semmelweis University, Budapest, Hungary; MTA-SE Tumor Progression Research Group, Budapest, Hungary.
Tibor
T
Krenacs
D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003198:Computer Simulation; D000072259:Connexin 26; D000075302:Connexin 30; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism*; D017630:Connexins / Q000235:genetics* / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046228:Microarray Analysis / Q000379:methods; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D000097002:Gap Junction beta-1 Protein
D000072259:Connexin 26; D000075302:Connexin 30; D018031:Connexin 43; D017630:Connexins; D000097002:Gap Junction beta-1 Protein; C500216:GJA1 protein, human; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; C082917:GJA3 protein, human