Progesterone receptor involvement in independent tumor growth in MPA-induced murine mammary adenocarcinomas

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 68; no. 1; pp. 11 - 21
• Main Authors: Montecchia, Marı́a Fernanda, Lamb, Caroline, Molinolo, Alfredo A., Luthy, Isabel A., Pazos, Patricia, Charreau, Eduardo, Vanzulli, Silvia, Lanari, Claudia
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 1999; Elsevier Science
• Subjects: Adenocarcinoma - chemically induced; Adenocarcinoma - drug therapy; Adenocarcinoma - metabolism; Androgens - metabolism; Animals; Antiprogestins; Antisense; Binding Sites; Biological and medical sciences; Estradiol - pharmacology; Female; Flutamide - pharmacology; Glucocorticoids - metabolism; Gonanes - pharmacology; Gynecology. Andrology. Obstetrics; Hormone Antagonists - pharmacology; Mammary adenocarcinomas; Mammary gland diseases; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Medroxyprogesterone Acetate - toxicity; Mice; Mice, Inbred BALB C; Mifepristone - pharmacology; Neoplasms, Hormone-Dependent - chemically induced; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - metabolism; Oligonucleotides, Antisense - pharmacology; Ovariectomy; Progesterone receptors; Receptors, Estrogen - metabolism; Receptors, Progesterone - antagonists & inhibitors; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Thymidine - metabolism; Tumor Cells, Cultured; Tumors; Mammary adenocarcinomas; Antiprogestins; Antisense; Mice; Progesterone receptors; Adenocarcinoma; Cell proliferation; Ligand binding; Animal model; Hormonodependence; Rodentia; Malignant tumor; Ovarian hormone; Mammary gland diseases; Vertebrata; Mammalia; Mouse; Mammary gland; Progesterone; Sex steroid hormone; Hormonal receptor
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/S0960-0760(98)00166-6

We have developed a model of hormonal carcinogenesis in BALB/c female mice, in which MPA induced ductal mammary adenocarcinomas, expressing high levels of estrogen and progesterone receptors (ER and PR). A series of tumor lines, retaining both PR and ER expression, were obtained from selected tumors, which are maintained by syngeneic passages. In this model progesterone behaves as the growth-stimulating hormone (progesterone-dependent or PD tumors), whereas estrogens induce tumor regression. Through selective treatments we were able to derive a series of progesterone-independent (PI) variants. These lines do not require progesterone treatment to grow in ovariectomized female BALB/c mice, but retain, however, the expression of ER and PR. The aim of this paper is to investigate a possible regulatory role of the progesterone receptor (PR) on PI tumor growth. ER and PR were detected by immunocytochemistry in all lines studied. They were also characterized using biochemical assays and Scatchard plots. No differences in K d of PR or ER were detected in PI variants. AR or GR were not detected in tumor samples using biochemical assays. Estradiol (5 mg silastic pellet) induced complete tumor regression in all tumors tested. We also evaluated the effects of different antiprogestins on tumor growth. Onapristone (10 mg/kg/day) and mifepristone (4.5 mg/kg/day) were able to induce complete tumor regression. The antiandrogen flutamide (5 mg silastic pellet) had no effect on tumor growth in agreement with the lack of androgen receptors. We used an in vitro approach to corroborate that the antiprogestin-induced inhibition was not attributable to an intrinsic effect. Cultures of a selected PI line were treated with PR antisense oligodeoxynucleotides (ASPR) to inhibit in vitro cell proliferation. A significant decrease of 3H-thymidine uptake was observed in cells of a PI line growing in the presence of 2.5% charcoalized fetal calf serum and 0.8–20 μg/ml ASPR. It can be concluded that the PR pathway is an essential path in the growth stimulation of PI tumors.