Triiodothyronine (T3) Upregulates the Expression of the Amphiregulin (AREG) Oncogene through Extranuclear Pathways in Breast Adenocarcinoma (MCF-7)

Presentation Number: SUN 265
Date of Presentation: April 2nd, 2017

Maria Teresa De Sibio*1, Fernanda Cristina Fontes Moretto2, Regiane Marques Castro Olimpio3, Miriane de Oliveira2, Bianca Mariani Gonçalves3, Lucas Solla Mathias3, Igor de Carvalho Depra4, Gilberto J. Paz-Filho5 and Celia R Nogueira6
1Botucatu School of Medicine, University of São Paulo State, Brazil, Botucatu, Brazil, 2Botucatu School of Medicine, University of São Paulo State, Brazil, Botucatu, BRAZIL, 3Botucatu School of Medicine, University of São Paulo State, Brazil, Botucatu, 4Botucatu School of Medicine, University of São Paulo State, Brazil., Dept .of Medicina, 5Australian National University, Acton, Australia, 6Botucatu School of Medicine, University of São Paulo State, Brazil., Botucatu



Introduction: Data from the literature suggests that triiodothyronine (T3) has a role in the development of breast cancer (BC), through the modulation of the expression of particular genes via classical nuclear, and non-classical extranuclear pathways. Several works led to the discovery of amphiregulin (AREG), a protein member of the epidermal growth factor (EGF) family that positively modulates the epidermal growth factor receptor (EGFR). When expressed, AREG induces mammary epithelium proliferation; thus, AREG is classified as an oncogene, with its expression related to several cancer types. However, the relationship between AREG expression and the presence of thyroid hormones remains largely unknown.

Objective: To evaluate whether T3 regulates the oncogene AREG expression, and determine the mechanism by which the modulation of AREG expression occurs.

Methods: MCF-7 adenocarcinoma cell lines were subjected to treatment with 10-8M T3 for 1h, alone or combined with either the PI3K inhibitor LY294002 (LY), the ERK/MAPK inhibitor PD98059 (PD), or the integrin αvβ3 inhibitor RGD peptide (RGD), which were added to the medium 1h before T3. AREG mRNA expression was assayed using RT-PCR. All experiments were repeated at three different moments for all treatments and times, between the second and third passage, in triplicate. For statistical analysis, we used ANOVA complemented with Tukey test and a minimum 5% significance was adopted.

Results: Our results show that T3 (12.9 ± 2.06) significantly elevated AREG gene expression levels related to the control group (1 ± 0.16). Nonetheless, when associated with a pathway inhibitor (T3+LY 7.91±0.69); (T3+PD 3.53±0.33) and (T3+ RGD 2.95±0.08), there was a significant downregulation of AREG expression, when compared to the T3 group (12.9 ± 2.06).

Conclusions: In this study, we demonstrate that T3 increases AREG gene expression through extranuclear pathways. The data obtained present a great potential for application, since the identification of new signaling pathways and other mecanisms by which thyroid hormones act can lead to the development of specific drugs, to activate or block such pathways, promoting desirable effects and blocking undesirable ones.


Nothing to Disclose: MTD, FCFM, RMCO, MDO, BMG, LSM, IDCD, GJP, CRN