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Androgens down-regulate bcl-2 protooncogene expression in ZR-75-1 human breast cancer cells
J Lapointe1, A Fournier, V Richard
1Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center and Laval University, Québec, Canada.
Abstract:
Although a large proportion of primary human breast cancers express the androgen receptor, and treatment with androgens exerts beneficial effects in women with breast cancer, the role and especially the mechanism of action of androgens in breast cancer development and growth are not well understood. The potential effect of androgens on bcl-2 protooncogene expression was investigated in a human breast cancer cell line whose proliferation is known to be inhibited by androgens. The estrogen-responsive ZR-75-1 cells were grown in the presence or absence of 5alpha-dihydrotestosterone (DHT), alone or in combination with 17beta-estradiol. DHT caused a marked down-regulation of Bcl-2 protein and messenger RNA levels in both the presence and absence of 17beta-estradiol. The inhibitory effect of DHT was completely prevented by coincubation with the pure antiandrogen hydroxyflutamide. The present data indicate that androgens can down-regulate bcl-2 protooncogene levels via an androgen receptor-mediated mechanism, thus providing a novel mechanism for their known inhibitory effect on breast cancer cell growth.
Insights
Androgens, like 5alpha-dihydrotestosterone (DHT), inhibit breast cancer cell growth by reducing Bcl-2 protein and messenger RNA levels. This effect is mediated through the androgen receptor, offering a new understanding of androgen action in breast cancer.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Androgen receptor (AR) is expressed in many human breast cancers.
- Androgen therapy shows beneficial effects in women with breast cancer.
- The precise role and mechanism of androgens in breast cancer remain unclear.
Purpose of the Study:
- To investigate the effect of androgens on bcl-2 protooncogene expression in human breast cancer cells.
- To elucidate the mechanism by which androgens inhibit breast cancer cell proliferation.
Main Methods:
- Utilized estrogen-responsive ZR-75-1 human breast cancer cells.
- Treated cells with 5alpha-dihydrotestosterone (DHT) alone or with 17beta-estradiol.
- Assessed Bcl-2 protein and messenger RNA levels.
- Investigated the role of the androgen receptor using the antiandrogen hydroxyflutamide.
Main Results:
- DHT significantly down-regulated Bcl-2 protein and messenger RNA levels.
- This down-regulation occurred irrespective of 17beta-estradiol presence.
- The antiandrogen hydroxyflutamide completely blocked the inhibitory effect of DHT.
- Results suggest an androgen receptor-mediated mechanism.
Conclusions:
- Androgens can inhibit breast cancer cell growth by down-regulating bcl-2 protooncogene expression.
- The androgen receptor mediates this inhibitory effect.
- This provides a novel mechanism for the known beneficial effects of androgens in breast cancer treatment.