Triiodothyronine (T3) induces HIF1A and TGFA expression in MCF7 cells by activating PI3K

Abstract

High expression levels of hypoxia inducing factor 1 alpha are related to mammary carcinogenesis. In previous studies, we demonstrated that expression of transforming growth factor alpha increases upon treatment with triiodothyronine, but this expression does not occur in cellular models that do not express the estrogen receptor, or when cells are co-treated with the anti-estrogen, tamoxifen. The aim of this study was to determine the effect of the hormone triiodothyronine on the expression of the genes HIF1A and TGFA in the breast cancer cell line MCF7. The cell line was subjected to treatment with triiodothyronine at the supraphysiological dose of 10(-8)M for 10min, 30min, 1h, and 4h in the presence or absence of actinomycin D, the gene expression inhibitor, cycloheximide, the protein synthesis inhibitor, and LY294002, the phosphoinositide 3 kinase inhibitor. HIF1A and TGFA mRNA expression was analyzed by reverse transcription polymerase chain reaction. For data analysis, we used analysis of variance complemented by Tukey test and an adopted minimum of 5% significance. We found that HIF1A and TGFA expression increased in the presence of triiodothyronine at all times studied. HIF1A expression decreased in triiodothyronine-treated cells when gene transcription was also inhibited; however, TGFA expression decreased after 10 and 30min of treatment even when transcription was not inhibited. We found that activation of PI3K was necessary for triiodothyronine to modulate HIF1A and TGFA expression.

Review of the possible association between thyroid and breast carcinoma

“…These factors are related to the genesis and development of BC. Moreover, thiiodothyronine (T3) exerts this effect by activating PI3K [ 40 ]. As shown in the 2002 study by Sumi Dinda et al, T3 may regulate the cell cycle progression and proliferation of T47D cells (an estrogen-responsive human ductal carcinoma cell line that expresses detectable levels of ER) by increasing the p53 levels and inducing pRb hyperphosphorylation via a common mechanism involving the ER and T3 receptor-mediated pathways [ 41 ].…”

The significance of TRIP11 and T3 signaling pathway in renal cancer progression and survival of patients.

“…1). We hypothesised that this T3 effect could be mediated by PI3K, previously shown to be activated by thyroid hormone [20,21]. To test this hypothesis, we pre-treated the cells with specific PI3K inhibitor, wortmannin.…”

The Association Between Breast Cancer and Thyroid Function: From Birth to Death

“…To determine the mechanisms of this phenomenon, many studies were conducted, which had controversial findings. The expression of hypoxia-inducing factor 1 alpha (HIF1A), a protein that regulates the transcription of cellular and developmental responses to hypoxia, is related to several cancers, including mammary carcinogenesis [67,68]. Transforming growth factor-alpha (TGFA) is a member of the epidermal growth factor family that stimulates mitosis and plays a role in cell proliferation, differentiation, and development [67,69].…”

“…Both HIF1A and TGFA can induce angiogenesis. T3 can stimulate the expression of these genes in the MCF7 BC cell line by activating the PI3K pathway [67]. Besides, MCF7 cell proliferation is promoted due to an increase in the activity of ER expression induced by T3 and T47D cells as an estrogen-responsive human ductal carcinoma cell lines, expressing detectable levels of ER.…”