Clinical relevance of pdcd4, a nuclear ErbB-2 target gene, in different breast cancer subtypes.

PEREYRA MG; CHIAUZZI V; FIGURELLI, SILVINA; SCHILLACI R; ELIZALDE PV; CHERVO, MF; MADERA S; BARCHUK, SABRINA; ROA JC; CORDO-RUSSO, ROSALÍA; AMASINO M; VENTURUTTI, L; PROIETTI CJ; GUZMÁN P; CHARREAU E.H

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

PDCD4 (programmed cell death 4) is a tumor suppressor gene involvedin metastasis in breast cancer (BC). We previously reportedthat ErbB-2 nuclear function as a transcription factor (TF) and alsoas a coactivator of TF Stat3, leads to increased microRNA-21 levels,therefore decreasing PDCD4 expression favouring metastasis.To explore PDCD4 clinical relevance in BC, we analyzed PDCD4expression by immunohistochemistry in 541 patients with primaryinvasive BC. We found that 34% of patients showed PDCD4 expressionand was associated with good prognosis (p=0.009). SurrogateBC subtypes include Luminal A (Lum A, estrogen and progesteronereceptor positive, ER+/PR+), Luminal B (Lum B, ER+/PR-), LumB-ErbB-2 positive (+), ErbB-2+-non luminal, and triple negative BC(TNBC, ER-/PR-/ErbB2-). PDCD4 expression was associated witha higher overall survival probability in patients with Lum A, Lum B,and ErbB-2+ subtypes, but not in TNBC (p=0.044, p=0.016, p=0.05,and p=0.40, respectively). Correlation of PDCD4 mRNA expressionand patient outcome using publicly available KM plotter database,showed similar results. Interestingly, we found that 80% (84/104)of TNBC patients lacked PDCD4 expression. Western blot showedthat PDCD4 levels were decreased in TNBC (MDA-MB-453, -231and -468) compared to Lum A cells. As our previous reports indicatedthat TNBC cells express NErbB-2 which modulates PDCD4levels, we explored the effects of NErbB-2 blockade in PDCD4 expressionby using ErbB-2ΔNLS mutant which acts as a dominantnegative inhibitor of endogenous NErbB-2. ErbB-2ΔNLS increasedPDCD4 levels in TNBC cells. We also found that in PDCD4 negativeTNBC patients NErbB-2 presence was associated with poorprognosis (p=0.031). Our findings stress the association in TNBCbetween high levels of NErbB-2, lack of PDCD4 expression, tumormetastasis and poor prognosis. We also reveal PDCD4 expressionas a marker of better clinical outcome in Lum A, Lum B and ErbB-2+BC subtypes.Keywords: Breast Cancer Subtypes, PDCD4, Clinical Biomarker,Nuclear ErbB-2, Triple Negative Breast CancerOur findings stress the association in TNBC between high levelsof NErbB-2, lack of PDCD4 expression, tumor metastasis and poorprognosis.