Trastuzumab inhibits pituitary tumor cell growth modulating the TGFB/SMAD 2/3 pathway

JUAN PABLO PETITI, LILIANA SOSA, FLORENCIA PICECH, PABLO PEREZ, GABRIELA MOYANO CRESPO, CAROLINA GUIDO, EUGENIA SABATINO, PEDRO GARCÍA, VERÓNICA BENGIÓ, PAULA ESTARIO, CELINA BERHARD, SILVINA GUTIÉRREZ, ANA DE PAUL, JORGE MUKDSI, ALICIA TORRES

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Investigación Clínica

In pituitary adenomas, early recurrences and resistance to conventionalpharmacotherapies are common, but the mechanismsinvolved are still not understood. The high expression of epidermalgrowth factor receptor 2 (HER2)/ extracellular signal-regulated kinase(ERK1/2) signal observed in human pituitary adenomas, togetherwith the low levels of the antimitogenic transforming growthfactor beta receptors (TbRs), encouraged us to evaluate the effectof the specific HER2 inhibition with trastuzumab on experimentalpituitary tumor cell growth and its effect on the antiproliferative responseto TGFb1. Trastuzumab decrease (p≤0.05) the pituitary tumorgrowth as well as the expression of ERK1/2 and the cell cycleregulators cyclin D1 and CDK4. The HER2/ERK1/2 pathway is anattractive therapeutic target, but its intricate relations with other signalingmodulators still need to be unraveled. Thus, we investigatedpossible cross-talk with TGFb signaling, which has not yet beenstudied in pituitary tumors. In tumoral GH3 cells, co-incubation withtrastuzumab and TGFb1 significantly decreased (p≤0.05) cell proliferation,and effect accompanied by reduction in ERK1/2 phosphorylationand an increase of SMAD2/3 activation. In addition, throughimmunoprecipitation assays, an increase in TGFbR1-SMAD2/3association was observed when cells were co-incubated with theinhibitor of the HER2/ERK1/2 pathway and TGFb1. These findingsindicate that blocking HER2 by trastuzumab inhibited pituitary tumorgrowth and modulated HER2/ERK1/2 signaling and consequentlythe anti-mitogenic TGFb1/TbRs/SMADs cascade. The imbalancebetween HER2 and TGFBRs expression observed in human adenomasand the response to trastuzumab on experimental tumorgrowth, may make the HER2/ERK1/2 pathway an attractive targetfor future pituitary adenoma therapy.Keywords: Pituitary adenoma, HER2, ERK1/2, TbRs, Smad2/3.