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An Ex vivo Model to Study Hormone Action in the Human Breast
Published on: January 8, 2015
Dehydroepiandrosterone antiestrogenic action through androgen receptor in MCF-7 human breast cancer cell line
G Boccuzzi1, M Di Monaco, E Brignardello
1Department of Clinical Pathophisiology, University of Turin, Italy.
Abstract:
The possible mechanisms of the inhibitory effect of Dehydroepiandrosterone (DHEA) on the estrogen-induced growth of MCF-7 human breast cancer cells were explored. The impairment of metabolic pathways, via the inhibition of glucose-6-phosphate dehydrogenase (G6PD) activity, was excluded: G6PD activity in MCF-7 homogenate was reduced by DHEA only at a very high concentration (50 microM), while no inhibitory action on the enzyme activity was detected when DHEA was added at the antimitotic concentrations (0.02-0.5 microM). A steroid receptor mediated effect was explored: DHEA might either activate androgen receptors (AR) or partially displace E2 from estrogen receptor (ER). The pure antiandrogens Flutamide and Hydroxyflutamide reversed the inhibitory effect of DHEA on MCF-7 cell growth, whereas both the nonsteroidal estrogen Diethylstilbestrol and the antiestrogen Tamoxifen were ineffective. Results demonstrate that the AR activation plays a pivotal role in the inhibitory action of DHEA on the E2-induced MCF-7 growth.
Insights
Dehydroepiandrosterone (DHEA) inhibits estrogen-induced breast cancer cell growth by activating androgen receptors (AR). This mechanism, not metabolic pathway impairment, is key to DHEA
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- Estrogen promotes the growth of MCF-7 human breast cancer cells.
- Dehydroepiandrosterone (DHEA) exhibits inhibitory effects on this growth.
- The precise mechanisms underlying DHEA's action require elucidation.
Purpose of the Study:
- To investigate the mechanisms by which Dehydroepiandrosterone (DHEA) inhibits estrogen-induced growth of MCF-7 human breast cancer cells.
- To differentiate between metabolic pathway inhibition and steroid receptor-mediated effects.
Main Methods:
- Assessing glucose-6-phosphate dehydrogenase (G6PD) activity in MCF-7 homogenate with and without DHEA.
- Evaluating the impact of DHEA on MCF-7 cell growth in the presence of antiandrogens (Flutamide, Hydroxyflutamide) and estrogen receptor modulators (Diethylstilbestrol, Tamoxifen).
Main Results:
- DHEA did not inhibit G6PD activity at physiologically relevant antimitotic concentrations.
- Pure antiandrogens Flutamide and Hydroxyflutamide reversed DHEA's inhibitory effect.
- Nonsteroidal estrogen Diethylstilbestrol and antiestrogen Tamoxifen did not affect DHEA's action.
Conclusions:
- Androgen receptor (AR) activation is a pivotal mechanism in DHEA's inhibition of estrogen-induced MCF-7 cell growth.
- Metabolic pathway impairment is not the primary mechanism.
- DHEA's anti-cancer effects in this model are mediated through AR signaling.
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