Horm Metab Res 2005; 37(8): 468-473
DOI: 10.1055/s-2005-870306
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Dose-dependent Changes of the Ratio of Apoptosis to Proliferation by Norethisterone and Medroxyprogesterone Acetate in Human Breast Epithelial Cells

H.  Seeger1 , V.  Rakov1 , A.  O.  Mueck1
  • 1Section of Endocrinology and Menopause, University Women’s Hospital, Tübingen, Germany
Further Information

Publication History

Received 17 December 2004

Accepted after revision 7 March 2005

Publication Date:
01 September 2005 (online)

Abstract

Objective: There is increasing evidence that adding progestogens to estrogen replacement therapy may do more harm than good; however, whether all progestogens act equally on breast cells is debatable. Apart from estrogens, mitogenic growth factors from stromal breast tissue are important in growth-regulation of breast cells, and may modify the response to progestogens. We investigated the effects of medroxyprogesterone acetate (MPA) as well as norethisterone (NET) in the presence of a growth factor mixture and/or estradiol in normal and cancerous human epithelial breast cells. Methods: MCF10A cells (human epithelial, estrogen- and progesterone-receptor negative, normal breast cells), HCC1500 (human estrogen and progesterone receptor-positive primary breast cancer cells) and MCF-7 cells (human estrogen and progesterone receptor-positive metastatic breast cancer cell line) were used in the experiments. The cells were incubated with progestogens at concentrations of 10 - 10 to 10 - 6 M for 7 days and growth factors (GFs), estradiol (E2) alone and a combination of GFs + E2. Cell proliferation rate was measured by ATP assay. Apoptosis was measured by cell death assay. Ratios of cell death : proliferation were calculated from these results. Results: In MCF10A cells growth factors elicited a decrease in the ratio of apoptosis to proliferation. This effect was further stimulated by the addition of MPA, whereas NET had no effect. In HCC cells growth factors and estradiol alone and in combination led to a reduction in the ratio. This effect could be partly reversed dose-dependently by the addition of MPA and NET, being more pronounced for MPA. Similar results were found for MCF-7 cells stimulated by estradiol. Conclusion: The results of our investigations demonstrate that there are differences between the two progestogens NET and MPA investigated with respect to their effects on normal and cancerous cells. By increasing the mitotic rate of normal epithelial cells, MPA may increase breast cancer risk in women when used in long-term treatment. In this respect NET reacts neutral. The mitosis of pre-existing cancerous cells may be partly inhibited by the addition of both progestogens. Thus, our results indicate that it is necessary to differentiate between normal and malignant breast cells concerning the assessment of progestogens as a risk factor for breast carcinogenesis.

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A. O. Mueck, M. D., Pharm. D., Ph. D.

Head of Section of Endocrinology and Menopause · University Women’s Hospital

Calwerstraße 7 · 72076 Tübingen · Germany

Fax: +49 (7071) 29 48 01 ·

Email: endo.meno@med.uni-tuebingen.de