The effects of progesterone, medroxyprogesterone acetate, and norethisterone on growth factor- and estradiol-treated human cancerous and noncancerous breast cells.
OBJECTIVE
Mitogenic growth factors from stromal breast tissue and estrogens are important in growth regulation of breast cells and may modify different responses dependent on the choice of progestogens. The effects of the acknowledged pharmacologically significantly different progestogens, progesterone, medroxyprogesterone acetate (MPA), and norethisterone, were investigated in breast cells treated with growth factor and/or estradiol, comparing normal and primary cancer cells for the first time.


METHODS
MCF10A (human epithelial, estrogen-receptor-negative and progesterone-receptor-negative normal breast cells) were incubated with progestogens at 1 microM and 100 nM for 7 days and epidermal growth factor, fibroblast growth factor, and insulin-like growth factor at 1 pM. HCC1500 (human estrogen-receptor-positive and progesterone-receptor-positive primary breast cancer cells) were incubated in the same way with growth factors and/or estradiol at 100 pM. Cell proliferation rate was measured by the ATP assay, whereas cell death was measured by photometric enzyme immunoassay. Ratios of cell death to proliferation were calculated from these results.


RESULTS
In combination with growth factors, MPA reduced the ratio in favor of a proliferative effect in MCF10A cells, followed by norethisterone. Progesterone had no significant effect on the growth factor response. In HCC1500 cells, MPA with growth factors increased the ratio favoring inhibition, norethisterone had a proliferative effect, and progesterone had no significant effect. In combination with estradiol, MPA increased the ratio to inhibition to the greatest extent, followed by norethisterone and progesterone at 1 muM. In combination with growth factors and estradiol, MPA and norethisterone both showed an inhibitory effect, whereas progesterone had no significant effect.


CONCLUSIONS
Certain progestogens are able to induce the proliferation of benign or malignant human breast cells independently of the effects of growth factors and estradiol. Therefore, the choice of progestogen may be important in terms of influencing a possible breast cancer risk.
Krämer
Elizabeth A
EA
Section of Endocrinology and Menopause, University Womens' Hospital, Tuebingen, Germany.
Seeger
Harald
H
Krämer
Bernhard
B
Wallwiener
Diethelm
D
Mueck
Alfred O
AO
D017209:Apoptosis / Q000187:drug effects; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D000077289:Letrozole; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D009640:Norethindrone / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D047072:Aromatase Inhibitors; D003271:Contraceptive Agents, Female; D004965:Estrogen Antagonists; D006133:Growth Substances; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; C016601:afimoxifene; D011374:Progesterone; D000077289:Letrozole; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone