Abstract
It has been well established that estrogen plays an important role in the progression and treatment of breast cancer. However, the role of triiodothyronine (T3) remains controversial. We have previously shown its capacity to stimulate the development of positive estrogen receptor breast carcinoma, induce the expression of genes (PR, TGF-alpha) normally stimulated by estradiol (E2), and suppress genes (TGF-beta) normally inhibited by E2. Since T3 regulates growth hormones, metabolism, and differentiation, it is important to verify its action on other genes normally induced by E2. Therefore, we used DNA microarrays to compare gene expression patterns in MCF-7 breast adenocarcinoma cells treated with E2 and T3. Several genes were modulated by both E2 and T3 in MCF-7 cells (Student's t-test, P < 0.05). Specifically, we found eight genes that were differentially expressed after treatment with both E2 and T3, including amphiregulin, fibulin 1, claudin 6, pericentriolar material 1, premature ovarian failure 1B, factor for adipocyte differentiation-104, sterile alpha motif domain containing 9, and likely ortholog of rat vacuole membrane protein 1 (fold change > 2.0, pFDR < 0.05). We confirmed our microarray results by real-time PCR. Our findings reveal that certain genes in MCF-7 cells can be regulated by both E2 and T3.
Highlights
Most breast cancer risk factors are associated with prolonged exposure of the mammary gland to high levels of estrogen
RNA samples extracted from triplicate samples of MCF-7 cells after 24 h of E2 or T3 treatment were analyzed for E2- or T3-regulated gene expression by comparing to cells treated with vehicle control
Some of the other genes that we identified as being regulated by E2 and T3 are directly involved in cell proliferation, such as EMP1, IFNAR2, VMP, FLJ20073, MYC, and AREG, and some are involved in nucleotide binding and/or protein binding, such as PFKFB3, APPBP2, SSFA2, and NALP7
Summary
Most breast cancer risk factors are associated with prolonged exposure of the mammary gland to high levels of estrogen. The involvement of thyroid hormones (TH) in the development and differentiation of normal breast tissue has been established [2,3,4] and epidemiological and experimental studies have associated TH pathologies with an increased risk of breast cancer, the role of TH remains controversial [5,6,7,8,9,10,11,12,13,14]. If not all, major triiodothyronine (T3) actions are mediated by specific high affinity nuclear receptors (thyroid receptor, TR), which are encoded by the two genes THRA and THRB that are ligand-regulated transcription factors that act via DNA response elements [17]. Recent results have revealed substantial changes in the expression profile of thyroid hormone receptors, suggesting that their deregulation may be involved in breast cancer development [18]
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