Long-term hormonal promotion overcomes genetic resistance to mammary cancer.
It is well known that ovarian steroids estradiol and progesterone play a vital role in the development of mammary cancer. Here, using the genetically highly resistant Copenhagen rats we demonstrate that sustained exogenous treatment with estradiol and progesterone overcomes genetic resistance to mammary cancer. It has been demonstrated that Copenhagen rats develop preneoplastic lesions upon exposure to carcinogens. However, these preneoplastic lesions fail to progress to ductal carcinomas in situ or overt mammary carcinomas. The preneoplastic lesions eventually decrease in number and are absent by 60 days post-carcinogen treatment. In the present study, we exposed 7-week-old female Copenhagen rats to N-methyl-N-nitrosourea (MNU; 50mg/kg BW). Immediately after MNU treatment the rats were divided into the following groups: (1) control; (2) 30 mg estradiol 17β; (3) 30 mg progesterone; and (4) 30 mg estradiol 17β plus 30 mg progesterone. All hormone treatments were administered via individual silastic pellets for a period of 9 months post-carcinogen treatment. The control animals displayed a low incidence of mammary cancer (10%). Hormone treatments produced significantly higher incidences of mammary cancer, with estradiol at 50%, progesterone at 65% and estradiol plus progesterone at 90%. Hormone treatment sustained the growth of the lesions induced by MNU by increasing expression of Areg, Bcl-2, Ccnd-1 and Vegf genes, while decreasing expression of Bad, Bax, Casp 3, 8, 9 and p53 genes. Furthermore, hormone treatment increased CCND-1 and PARP proteins levels. The data clearly demonstrates that hormonal environment supports mammary cancer progression by increasing cell proliferation, and angiogenesis while inhibiting apoptosis.
Rajkumar
Lakshmanaswamy
L
Center of Excellence in Cancer Research, Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, 5001 El Paso Drive, El Paso, TX 79905, USA. rajkumar.lakshmanaswamy@ttuhsc.edu
Arumugam
Arunkumar
A
Elsayed
Ahmed
A
Schecter
Scott
S
Kotkowski
Eithan
E
Castillo
Ruth
R
de la Torre
Aleyah
A
Hernandez
Cecilio
C
D000818:Animals; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D020022:Genetic Predisposition to Disease; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008770:Methylnitrosourea; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D011374:Progesterone; D004958:Estradiol; D008770:Methylnitrosourea