Pineal melatonin inhibition of tumor promotion in the N-nitroso-N-methylurea model of mammary carcinogenesis: potential involvement of antiestrogenic mechanisms in vivo.
The N-methyl-N-nitrosourea (NMU) model of hormone-responsive rat mammary carcinogenesis was used to address the hypothesis that melatonin (Mel), the principle hormone of the pineal gland, inhibits tumorigenesis by acting as an anti-promoting rather than an anti-initiating agent. Daily late-afternoon injections of Mel (500 micrograms/day), restricted to the initiation phase of NMU mammary tumorigenesis, were ineffective in altering tumor growth over a 20-week period. When Mel treatment was delayed for 4 weeks after NMU and then continued through the remainder of the promotion phase, only tumor number was significantly lower than in controls. However, when Mel injections encompassed the entire promotion phase, both tumor incidence and number were significantly lower than in the controls. Although elimination of the endogenous Mel signal via pinealectomy promoted tumor growth, the effect was not statistically significant. Serum levels of estradiol and tumor estrogen receptor content were unaltered by either Mel or pinealectomy. While Mel treatment failed to affect circulating prolactin levels, pinealectomy caused a two-fold increase in serum prolactin. The estradiol-stimulated recrudescence of tumors following ovariectomy was completely blocked by either 20, 100 or 500 micrograms Mel/day or tamoxifen (20 micrograms/day). Thus, Mel appears to be an anti-promoting hormone that may antagonize the tumor-promoting actions of estradiol in this model of mammary tumorigenesis.
Blask
D E
DE
Department of Anatomy, University of Arizona, Tucson 85724.
Pelletier
D B
DB
Hill
S M
SM
Lemus-Wilson
A
A
Grosso
D S
DS
Wilson
S T
ST
Wise
M E
ME
D000818:Animals; D004195:Disease Models, Animal; D004958:Estradiol / Q000097:blood; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D008770:Methylnitrosourea; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D010052:Ovariectomy; D010870:Pineal Gland / Q000378:metabolism / Q000601:surgery; D011388:Prolactin / Q000097:blood; D011863:Radioimmunoassay; D011960:Receptors, Estrogen / Q000096:biosynthesis; D013629:Tamoxifen / Q000494:pharmacology
D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; D008770:Methylnitrosourea; D011388:Prolactin; D008550:Melatonin