ESTROGEN MITOGENIC ACTION. II. NEGATIVE REGULATION OF THE STEROID HORMONE–RESPONSIVE GROWTH OF CELL LINES DERIVED FROM HUMAN AND RODENT TARGET TISSUE TUMORS AND CONCEPTUAL IMPLICATIONS

• Published in: In vitro cellular & developmental biology. Animal Vol. 36; no. 7; pp. 428 - 446
• Main Authors: SIRBASKU, DAVID A, MORENO-CUEVAS, JORGE E
• Format: Journal Article
• Language: English
• Published: Germany Society for In Vitro Biology 01.07.2000
• Subjects: androgens; Animals; Breast cancer; Breast Neoplasms - chemistry; Breast Neoplasms - pathology; Cell Division - drug effects; Cell growth; CELL GROWTH/DIFFERENTIATION/APOPTOSIS; Cell lines; cortisol; Cricetinae; Culture Media; epidermal growth factor; Epidermal Growth Factor - pharmacology; Estradiol - pharmacology; Estrogen Antagonists - blood; Estrogens; Female; Gonadal Steroid Hormones - pharmacology; hamster kidney tumors; Hormonal regulation; human breast cancer; human prostate cancer; Humans; Hydrocortisone - pharmacology; Insulin - pharmacology; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor II - pharmacology; insulin-like growth factors; Kidney Neoplasms - pathology; Male; Mammary Neoplasms, Experimental - pathology; Mesocricetus; Neoplasms - pathology; Pituitary neoplasms; Pituitary Neoplasms - pathology; progesterone; Progesterone - pharmacology; Prostatic Neoplasms - pathology; rat pituitary tumors; Rats; Receptors, Estrogen - analysis; serum inhibitor; Steroid hormones; Steroids; Testosterone - pharmacology; transforming growth factor alpha; Transforming Growth Factor alpha - pharmacology; transforming growth factor beta; Tumor cell line; Tumor Cells, Cultured; Tumors
• ISSN: 1071-2690; 1543-706X; 1543-706X
• DOI: 10.1290/1071-2690(2000)036<0428:EMAINR>2.0.CO;2

In an accompanying report (Moreno-Cuevas, J. E.; Sirbasku, D. A., In Vitro Cell. Dev. Biol.; 2000), we demonstrated 80-fold estrogen mitogenic effects with MTW9/PL2 rat mammary tumor cells in cultures supplemented with charcoal–dextran-treated serum. All sera tested contained an estrogen reversible inhibitor(s). The purpose of this report is to extend those observations to additional sex steroid–responsive human and rodent cell lines. Every line tested showed a biphasic response to hormone-depleted serum. Concentrations of ≤10% (v/v) promoted substantive growth. At higher concentrations, serum was progressively inhibitory. With estrogen receptor–positive (ER+) human breast cancer cells, rat pituitary tumor cells, and Syrian hamster kidney tumor cells, 50% (v/v) serum caused significant inhibition, which was reversed by very low physiologic concentrations of estrogens. This same pattern was observed with the steroid hormone–responsive LNCaP human prostatic carcinoma cells. Because steroid hormone mitogenic effects are now easily demonstrable using our new methods, the identification of positive results has nullified our original endocrine estromedin hypothesis. We also evaluated autocrine/paracrine growth factor models of estrogen-responsive growth. We asked if insulin-like growth factors I and II, insulin, transforming growth factor alpha, or epidermal growth factor substituted for the positive effects of estrogens. Growth factors did not reverse the serum-caused inhibition. We asked also if transforming growth factor beta (TGFβ) substituted for the serum-borne inhibitor. TGFβ did not substitute. Altogether, our results are most consistent with the concept of a unique serum-borne inhibitor as has been proposed in the estrocolyone model. However, the aspect of the estrocolyone model related to steroid hormone mechanism of action requires more evaluation. The effects of sex steroids at picomolar concentrations may reflect mediation via inhibitor “activated” intracellular signaling pathways.