ICEECE2012 Oral Communications Endocrine Tumours & Translation (6 abstracts)
The central role of estrogen receptor α in IGF2 dependent adrenocortical carcinoma (ACC) cell proliferation suggests the use of selective estrogen receptor modulators (SERMs) for the treatment of ACC
R. Sirianni 1 , A. Chimento 1 , A. De Luca 1 , L. Cerquetti 4 , G. Carpinelli 5 , F. Fallo 2 , C. Pilon 2 , G. Arnaldi 3 , A. Stigliano 4 & V. Pezzi 1
1University of Calabria, Rende, Italy; 2University of Padova, Padova, Italy; 3University of Ancona, Ancona, Italy; 4University of Roma Sapienza, Roma, Italy; 5Istituto Superiore di Sanità, Roma, Italy.
Adrenocortical Cancer (ACC) is characterized by an increased production of insulin-like growth factor 2 (IGF2) and by estrogen receptor (ER) α up-regulation. Aim of this study was to define IGF2 and estrogen signaling interactions in ACC, in order to give new indications for a better therapy. To this aim we used H295R cells and human ACC tissues which display common features: IGF2 activation of downstream effector pathways and over-expression of estrogen-related genes including ERα and aromatase, the enzyme required for estrogen production. We demonstrated that IGF2 controls expression of steroidogenic factor 1 (SF-1), that in turn increases aromatase transcription. 17β-estradiol (E2) bound to ERα up-regulated IGF1R expression as a consequence of increased pCREB binding to IGF1R promoter. On the other hand, E2 and PPT (a selective ERα agonist) stimulated IGF1R phosphorylation and caused ERK1/2 and AKT activation. In the E2-dependent IGF1R transactivation we found the involvement of the scaffold protein PELP1/MNAR which acted as an adaptor protein for connecting ERα-IGF1R-Src-ERK1/2-AKT. These data suggest the ability for estrogens to activate IGF1R-downstream pathways even in the absence of IGF2. Furthermore, ERα regulated E2- and IGF2-induced cyclin D1 expression, a gene controlling cell cycle progression overexpressed in ACC. Silencing ERα significantly blocked the ability of E2 and IGF2 to induce cell proliferation more effectively than an anti-IGF1R monoclonal antibody, as used in phase I clinical trials. We also utilized H295R cells to generate xenografts in athymic nude mice to demonstrate the ability of SERMs such as tamoxifen to control ACC growth in vivo. Tamoxifen therapy significantly inhibited tumor growth further indicating that ERα contributes to the pathogenesis of ACC. These findings establish a critical role for ERα in IGF2-dependent ACC proliferation and provide rationale for targeting ERα (or PELP1) to control the proliferation of adrenocortical carcinoma.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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