Estradiol and progesterone can prevent rat mammary cancer when administered concomitantly with carcinogen but do not modify surviving tumor histology, estrogen receptor alpha status or Ha-ras mutation frequency.
An early full-term pregnancy is protective against mammary cancer in both humans and rodents. Treating rats with two hormones of pregnancy, estradiol and progesterone, for 5 weeks renders the rat mammary glands refractory to carcinogenesis. Our objectives was to determine if a shortened regimen (3 weeks) would be as effective as the 5-week regimen and to determine if the mammary gland was vulnerable to carcinogenic insult during the hormone treatments. We also examined cancers that survived the chemopreventive regimen to see if those tumors were particularly aggressive compared to control tumors (i.e., less differentiated, estrogen receptor alpha (ER alpha)-negative or harbored mutations in Ha-ras). In the first experiment, Lewis rats were injected with N-methyl-N-nitrosourea (MNU, 50 mg/kg) at 50 days of age. At 60 days of age, the rats were either mated and allowed to nurse their young for 3 weeks, treated with hormone vehicle for 5 weeks, or 17 beta-estradiol (E, 20 micrograms) and progesterone (P, 4 mg) 5 times per week for 3 or 5 weeks. All the rats exposed to MNU but not estradiol and progesterone developed multiple mammary cancers. Pregnancy reduced multiplicity to 0.40 cancers/rat. Treatments of estradiol and progesterone for 3 or 5 weeks reduced cancer multiplicity and increased latency to a similar degree as pregnancy. Mammary cancers from each group displayed a similar spectra of histologic class, estrogen receptor alpha (ER alpha) content and Ha-ras mutation status. In the second experiment, 50-day-old rats were treated for five weeks with either estradiol and progesterone or vehicle as above beginning at 60 days of age and treated with MNU at 50, 64, 78 or 92 days of age. In each case, estradiol and progesterone treatments resulted in significantly reduced mammary tumor frequency. These results demonstrate that a three-week regimen of estradiol and progesterone can protect the mammary gland from chemically-induced carcinogenesis even when carcinogen exposure occurs concomitant with estradiol and progesterone stimulation.
Swanson
Steven M
SM
Department of Medicinal Chemistry & Pharmacognosy, Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612-7231, USA. swanson@uic.edu
Christov
Konstantin
K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000037:antagonists & inhibitors; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008770:Methylnitrosourea; D009154:Mutation; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D011960:Receptors, Estrogen / Q000096:biosynthesis*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D011374:Progesterone; D004958:Estradiol; D008770:Methylnitrosourea