Down-regulation of the candidate tumor suppressor gene PAR-4 is associated with poor prognosis in breast cancer.
Substantial experimental evidence indicates that PAWR gene (PKC apoptosis WT1 regulator; also named PAR-4, prostate apoptosis response-4) is a central player in cancer cell survival and a potential target for cancer-selective targeted therapeutics. However, little is known about the role of PAR-4 in breast cancer. We investigated the possible role of PAR-4 expression in breast cancer. IHC results on tissue microarrays containing 1,161 primary breast tumor samples showed that 57% (571/995) of analyzable cases were negative for PAR-4 nuclear staining. Down-regulation of nuclear PAR-4 protein expression predicted a poor prognosis for breast cancer patients (OS; P=0.041, log-rank test). PAR-4 down-regulation also correlates with poor survival in the group of patients with luminal A subtype breast cancer (P=0.028). Additionally, in this large series of breast cancer patients, we show that ERBB2/HER2, EGFR and pAKT protein expression are significantly associated with shorter disease-free survival and overall survival, but the prognosis was even worse for HER2-positive, EGFR-positive or pAKT-positive breast cancer patients with tumors negative for nuclear PAR-4 expression. Furthermore, using three-dimensional (3D) cell culture we provide preliminary results showing that PAR-4 is highly expressed in the MCF10A cells inside the acini structure, suggesting that PAR-4 might have a role in the lumen acini formation. Taken together, our results provide, for the first time, evidence that PAR-4 may have a role in the process of the mammary gland morphogenesis and its functional inactivation is associated with tumor aggressive phenotype and might represent an additional prognostic and predictive marker for breast cancer.
Nagai
Maria Aparecida
MA
Disciplina de Oncologia, Departamento de Radiologia da Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455, 4 degrees andar, CEP 01246-903, São Paulo, Brazil. nagai@usp.br
Gerhard
Renê
R
Salaorni
Sibeli
S
Fregnani
José Humberto Tavares Guerreiro
JH
Nonogaki
Suely
S
Netto
Mário Mourão
MM
Soares
Fernando Augusto
FA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D016130:Immunophenotyping; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D055815:Young Adult
D051017:Apoptosis Regulatory Proteins; C101296:prostate apoptosis response-4 protein