Dehydroepiandrosterone inhibits the progression phase of mammary carcinogenesis by inducing cellular senescence via a p16-dependent but p53-independent mechanism.
BACKGROUND
Dehydroepiandrosterone (DHEA), an adrenal 17-ketosteroid, is a precursor of testosterone and 17beta-estradiol. Studies have shown that DHEA inhibits carcinogenesis in mammary gland and prostate as well as other organs, a process that is not hormone dependent. Little is known about the molecular mechanisms of DHEA-mediated inhibition of the neoplastic process. Here we examine whether DHEA and its analog DHEA 8354 can suppress the progression of hyperplastic and premalignant (carcinoma in situ) lesions in mammary gland toward malignant tumors and the cellular mechanisms involved.


METHODS
Rats were treated with N-nitroso-N-methylurea and allowed to develop mammary hyperplastic and premalignant lesions with a maximum frequency 6 weeks after carcinogen administration. The animals were then given DHEA or DHEA 8354 in the diet at 125 or 1,000 mg/kg diet for 6 weeks. The effect of these agents on induction of apoptosis, senescence, cell proliferation, tumor burden and various effectors of cellular signaling were determined.


RESULTS
Both agents induced a dose-dependent decrease in tumor multiplicity and in tumor burden. In addition they induced a senescent phenotype in tumor cells, inhibited cell proliferation and increased the number of apoptotic cells. The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action.


CONCLUSIONS
We provide evidence that DHEA and DHEA 8354 can suppress mammary carcinogenesis by altering various cellular functions, inducing cellular senescence, in tumor cells with the potential involvement of p16 and p21 in mediating these effects.
Shilkaitis
Anne
A
Department of Surgical Oncology, University of Illinois, 840 S, Wood Str, Chicago, IL 60612, USA. anneshil@uic.edu
Green
Albert
A
Punj
Vasu
V
Steele
Vernon
V
Lubet
Ronald
R
Christov
Konstantin
K
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000477:Alkylating Agents / Q000008:administration & dosage; D000818:Animals; D001943:Breast Neoplasms / Q000517:prevention & control*; D002278:Carcinoma in Situ / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence / Q000187:drug effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000276:Adjuvants, Immunologic; D000477:Alkylating Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; D003687:Dehydroepiandrosterone; D008770:Methylnitrosourea; C106219:5-androstene-16-fluoro-17-one