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Tamoxifen inhibits transforming growth factor-alpha gene expression in human breast carcinoma samples treated with
S J Conde1, R A M Luvizotto, M T Síbio
1Division of Endocrinology and Metabolism, Department of Medical Clinic, UNESP, Botucatu, Brazil.
Objectives:
To examine the effects of triiodothyronine (T3), 17beta-estradiol (E2), and tamoxifen (TAM) on transforming growth factor (TGF)-alpha gene expression in primary breast cancer cell cultures and interactions between the different treatments.
Methods And Results:
Patients included in the study (no.=12) had been newly diagnosed with breast cancer. Fresh human breast carcinoma tissue was cut into 0.3- mm slices. These slices were placed in six 35-mm dishes on 2-ml organ culture medium. Dishes received the following treatments: dish 1: ethanol; dish 2: T3; dish 3: T3+TAM; dish 4: TAM; dish 5: E2; dish 6: E2+TAM. TGF-alpha mRNA content was normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA levels. All tissues included in this study were positive for estrogen receptor (ER) and thyroid hormone receptor expression. Treatment with T3 for 48 h significantly increased TGF-alpha mRNA levels compared to controls (15-fold), and concomitant treatment with TAM reduced expression to 3.4-fold compared to controls. When only TAM was added to the culture medium, TGF-alpha mRNA expression increased 5.3-fold, significantly higher than with all other treatment modalities.
Conclusion:
We demonstrate that TGF-alpha mRNA expression is more efficiently upregulated by T3 than E2. Concomitant treatment with TAM had a mitigating effect on the T3 effect, while E2 induced TGF-alpha upregulation. Our findings show some similarities between primary culture and breast cancer cell lines, but also some important differences: a) induction of TGF-alpha, a mitogenic protein, by TAM; b) a differential effect of TAM that may depend on relative expression of ER alpha and beta; and c) supraphysiological doses of T3 may induce mitogenic signals in breast cancer tissue under conditions of low circulating E2.
Insights
Triiodothyronine (T3) significantly increased transforming growth factor-alpha (TGF-alpha) mRNA in breast cancer cells. Tamoxifen (TAM) mitigated T3
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Estrogen receptor (ER) and thyroid hormone receptor expression are common in breast cancer.
- Transforming growth factor-alpha (TGF-alpha) is a mitogenic protein implicated in cancer progression.
Purpose of the Study:
- To investigate the effects of triiodothyronine (T3), 17beta-estradiol (E2), and tamoxifen (TAM) on TGF-alpha gene expression in primary breast cancer.
- To explore the interactions between these treatments on TGF-alpha expression.
Main Methods:
- Primary human breast carcinoma tissues were cultured.
- Tissues were treated with T3, E2, TAM, or combinations thereof.
- TGF-alpha mRNA levels were quantified via quantitative real-time PCR.
Main Results:
- T3 treatment significantly upregulated TGF-alpha mRNA (15-fold increase).
- Concomitant TAM treatment reduced T3-induced TGF-alpha expression (3.4-fold increase).
- Tamoxifen alone increased TGF-alpha mRNA expression (5.3-fold increase).
Conclusions:
- T3 is a more potent inducer of TGF-alpha mRNA than E2 in breast cancer primary cultures.
- TAM exhibits a mitigating effect on T3-induced TGF-alpha upregulation.
- TAM alone can induce TGF-alpha, suggesting a potential mitogenic role independent of E2, possibly influenced by ER subtypes.
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