Induction of mammary adenocarcinomas by medroxyprogesterone acetate in BALBc female mice

Lanari, Claudia; Molinolo, Alfredo A.; Pasqualini, Christiane Dosne

doi:10.1016/0304-3835(86)90027-3

Cited by 89 publications

(58 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They showed (personal communication) that C4HD murine cells inoculated into BALB/c mice developed into substantial palpable tumors if treated with 5aP (40 mg depot). Tumor growth rate was about the same (or slightly higher) with 5aP as with an equivalent dose of medroxyprogesterone acetate, a known tumor inducer in this model (Lanari et al 1986). Secondly, in terms of potentially preventing, suppressing, or regressing breast tumors, more attention (both in vivo and in vitro) needs to be directed at the presumptive anti-cancer P metabolite, 3aHP, as well as 5a-reductase inhibitors.…”

Section: Summary Significance and Future Prospectsmentioning

confidence: 52%

Progesterone metabolites in breast cancer

Wiebe¹

2006

Endocr Relat Cancer

View full text Add to dashboard Cite

In the 70 years since progesterone (P) was identified in corpus luteum extracts, its metabolism has been examined extensively in many tissues and cell lines from numerous species. In addition to the reproductive tissues and adrenals, every other tissue that has been investigated appears to have one or more P-metabolizing enzyme, each of which is specific for a particular site on the P molecule. In the past, the actions of the P metabolizing enzymes generally have been equated to a means of reducing the P concentration in the tissue microenvironment, and the products have been dismissed as inactive waste metabolites. In human breast tissues and cell lines, the following P-metabolizing enzymes have been identified: 5a-reductase, 3a-hydroxysteroid oxidoreductase (3a-HSO), 3b-HSO, 20a-HSO, and 6a-hydroxylase. Rather than providing diverse pathways for inactivating and controlling the concentration of P in breast tissue microenvironments, it is proposed that the enzymes act directly on P to produce two types of autocrines/paracrines with opposing regulatory roles in breast cancer. Evidence is reviewed which shows that P is directly converted to the 4-pregnenes, 3a-hydroxy-4-pregnen-20-one (3a-dihydroprogesterone; 3aHP) and 20a-dihydro-progesterone (20aHP), by the actions of 3a-HSO and 20a-HSO respectively and to the 5a-pregnane, 5a-pregnane-3,20-dione(5a-dihydroprogesterone; 5aP), by the irreversible action of 5a-reductase. In vitro studies on a number of breast cell lines indicate that 3aHP promotes normalcy by downregulating cell proliferation and detachment, whereas 5aP promotes mitogenesis and metastasis by stimulating cell proliferation and detachment. The hormones bind to novel, separate, and specific plasma membrane-based receptors and influence opposing actions on mitosis, apoptosis, and cytoskeletal and adhesion plaque molecules via cell signaling pathways. In normal tissue, the ratio of 4-pregnenes:5a-pregnanes is high because of high P 3a-and 20a-HSO activities/expression and low P 5a-reductase activity/expression. In breast tumor tissue and tumorigenic cell lines, the ratio is reversed in favor of the 5a-pregnanes because of altered P-metabolizing enzyme activities/expression. The evidence suggests that the promotion of breast cancer is related to changes in in situ concentrations of cancerinhibiting and -promoting P metabolites. Current estrogen-based theories and therapies apply to only a fraction of all breast cancers; the majority (about two-thirds) of breast cancer cases are estrogeninsensitive and have lacked endocrine explanations. As the P metabolites, 5aP and 3aHP, have been shown to act with equal efficacy on all breast cell lines tested, regardless of their tumorigenicity, estrogen sensitivity, and estrogen receptor/progesterone receptor status, it is proposed that they offer a new hormonal basis for all forms of breast cancer. New diagnostic and therapeutic possibilities for breast cancer progression, control, regression, and prevention are suggested.

show abstract

Section: Summary Significance and Future Prospectsmentioning

confidence: 52%

Progesterone metabolites in breast cancer

Wiebe¹

2006

Endocr Relat Cancer

View full text Add to dashboard Cite

show abstract

“…All animal studies were conducted in accordance with the highest standards of animal care as outlined in the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Institute of Biology and Experimental Medicine of Buenos Aires Animal Research Committee. Hormone-dependent ductal tumor line C4HD and hormoneindependent line 60 were originated in mice treated with 40 mg of MPA (Medrosterona; Laboratorios Gador) every 3 mo for 1 year and have been maintained by serial transplantation in animals treated with 40-mg s.c. MPA depot in the flank opposite that of tumor inoculum (19,21,22,30). C4HD tumor line is of ductal origin and expresses progesterone and estrogen receptors (19,21,22,30).…”

Section: Animals and Tumorsmentioning

confidence: 99%

“…Hormone-dependent ductal tumor line C4HD and hormoneindependent line 60 were originated in mice treated with 40 mg of MPA (Medrosterona; Laboratorios Gador) every 3 mo for 1 year and have been maintained by serial transplantation in animals treated with 40-mg s.c. MPA depot in the flank opposite that of tumor inoculum (19,21,22,30). C4HD tumor line is of ductal origin and expresses progesterone and estrogen receptors (19,21,22,30). Line 60 is of lobular origin and does not express progesterone and estrogen receptors (31).…”

Section: Animals and Tumorsmentioning

confidence: 99%

See 1 more Smart Citation

Immunization with Murine Breast Cancer Cells Treated with Antisense Oligodeoxynucleotides to Type I Insulin-Like Growth Factor Receptor Induced an Antitumoral Effect Mediated by a CD8+ Response Involving Fas/Fas Ligand Cytotoxic Pathway

Schillaci

Salatino

Cassataro

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

We have demonstrated that in vivo administration of phosphorothioate antisense oligodeoxynucleotides (AS[S]ODNs) to type I insulin-like growth factor receptor (IGF-IR) mRNA resulted in inhibition of C4HD breast cancer growth in BALB/c mice. The present study focused on whether in vivo administration of C4HD tumor cells pretreated with IGF-IR AS[S]ODN and irradiated could provide protection against C4HD wild-type tumor challenge and also on elucidating the mechanism mediating this effect. Our results showed that mice immunized with IGF-IR AS[S]ODN-treated C4HD cells experienced a growth inhibition of 53.4%, 61.6%, and 60.2% when compared with PBS-treated mice, wild-type C4HD cell-injected mice, or phosphorothioate sense oligodeoxynucleotide-treated C4HD cell-injected mice, respectively. The protective effect was C4HD-specific, because no cross-protection was observed against other syngeneic mammary tumor lines. The lack of protection against tumor formation in nude mice indicated that T cells were involved in the antitumoral response. Furthermore, cytotoxicity and splenocyte proliferation assays demonstrated that a cellular CD8+-dependent immune response, acting through the Fas/Fas ligand death pathway, could be mediating the antitumor effect induced by immunization with AS[S]ODN-treated cells. Immunization also induced splenocytes to produce Ag-dependent IFN-γ, indicating the presence of a type 1 response. We demonstrated for the first time that IGF-IR AS[S]ODN treatment of breast cancer cells induced expression of CD86 and heat shock protein 70 molecules, both involved in the induction of the immunogenic phenotype. Immunization with these tumor immunogens imparted protection against parental tumor growth through activation of a specific immune response.

show abstract

“…It is very likely that mammary growth hormone production has direct or indirect promoting effects on mammary tumorgenesis. Although a stimulating effect of progestins on mammary tumour formation has been reported in cats (15), rhesus monkeys (30), and mice (12), the role of progestins in mammary tumorgenesis in women is still open to discussion (24,29,32).…”

Section: Introductionmentioning

confidence: 99%

Comparison of the histological changes in the dog after treatment with the progestins medroxyprogesterone acetate and proligestone

Garderen²,

Mol³

et al. 1995

Veterinary Quarterly

View full text Add to dashboard Cite

ligestone (PROL). Depot preparations of MPA or PROL were administered (SC) at 3-week intervals in two groups of seven ovariohysterectomized beagle dogs, after which three dogs of each group were killed. After a 6-month period without hormone treatment during which recovery was studied, the remaining dogs received five additional injections at the same interval and were subsequently killed. Tissue samples of four intact female beagle dogs served as controls.Progestin treatment resulted in atrophy of the adrenal cortex. In both MPA-and PROL-treated dogs, the thickness of the combined zona fasciculata and reticularis was There were no significant differences in the frequencies of the various abnormalities between MPA-and PROLtreated dogs. Our findings correspond with the clinical and biochemical results after treatment of dogs with MPA and PROL. The high incidence of mammary tumours might be associated with our recent finding that in the dog progestins induce ectopic production of growth hormone in the mammary gland. The dog might be a good model for further studies on hormonally induced breast cancers.

show abstract

Induction of mammary adenocarcinomas by medroxyprogesterone acetate in BALBc female mice

Cited by 89 publications

References 8 publications

Progesterone metabolites in breast cancer

Progesterone metabolites in breast cancer

Immunization with Murine Breast Cancer Cells Treated with Antisense Oligodeoxynucleotides to Type I Insulin-Like Growth Factor Receptor Induced an Antitumoral Effect Mediated by a CD8+ Response Involving Fas/Fas Ligand Cytotoxic Pathway

Comparison of the histological changes in the dog after treatment with the progestins medroxyprogesterone acetate and proligestone

Contact Info

Product

Resources

About