Subtype-specific alterations of the Wnt signaling pathway in breast cancer: clinical and prognostic significance.
The aim of the study is to understand the importance of the Wnt/β-catenin pathway in the development of breast cancer (BC) and its association with different clinicopathological parameters. Alterations (deletion/methylation/expression) of some Wnt/β-catenin pathway antagonists like APC, SFRP1/2, CDH1 and activator β-catenin (CTNNB1) were analyzed in primary BC in Indian patients. High frequencies (65-70%) of overall alterations (deletion/methylation) of the antagonists were seen in the BC samples. Also, 99% (156/158) of the samples showed alterations in any one of the genes, indicating the importance of this pathway in the development of this tumor. Co-alterations of these genes were observed in 30% of samples, with significantly high alterations in late-onset (37%) and estrogen receptor (ER)-/progesterone receptor (PR)- (37%) BC compared with early onset (21%) and ER/PR+ (18%) BC samples, respectively. Significantly high (P-value = 0.001-0.02) alterations of APC and CDH1 genes were seen in ER-/PR- BC compared with ER/PR+ BC. Immunohistochemical analysis showed reduced expression of the Wnt antagonists in BC concordant with their molecular alterations. Nuclear localization of β-catenin showed significant association with alterations in the antagonists and was also significantly high in the ER-/PR- BC samples. Alterations of SFRP2 coupled with a late clinical stage and low/nulliparity predicted the worst prognosis in BC patients. Therefore, the present study suggests that cumulative alterations in more than one Wnt antagonist along with increased nuclear accumulation of β-catenin play an important role in the development of BC and have significant clinical as well as prognostic importance.
Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata, India.
Nupur
N
Mukherjee
Nilanjana
N
Bhattacharya
Neyaz
N
Alam
Anup
A
Roy
Susanta
S
Roychoudhury
Chinmay K
CK
Panda
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008745:Methylation; D008875:Middle Aged; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D025601:Adenomatous Polyposis Coli Protein; D015703:Antigens, CD; D015820:Cadherins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D051153:Wnt Proteins; D051176:beta Catenin; C555337:APC protein, human; C513384:CDH1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human