Cell proliferation, apoptosis, and expression of cyclin D1 and cyclin E as potential biomarkers in tamoxifen-treated mammary tumors.
Tamoxifen has been widely used for treatment, and more recently, for the prevention of breast cancer. Since breast carcinomas are composed of heterogeneous populations of estrogen receptor-positive (ER+) cells, we hypothesized that tamoxifen may suppress tumor growth by differentially affecting cell proliferation and apoptosis. ER+ mammary tumors were induced in Sprague-Dawley rats by N-methyl-N-nitrosourea (MNU) and when they became palpable, the animals were treated for 5, 10, or 20 days with tamoxifen, 1.0 mg/kg body weight. Tamoxifen induced a time-dependent decrease in proliferating (BrdU-labeled) cells, arrested the cells in G1/0 phase, and differentially decreased the cyclin E and cyclin D1 expression at mRNA and protein levels. In the same tumors, apoptotic cells increased during the first 10 days of treatment, but their number remained unchanged with extension of the treatment to 20 days. Thus, we provide data that tamoxifen may differentially affect cell proliferation and apoptosis in mammary tumors and that the expression levels of cyclin D1 and cyclin E might also be considered potential intermediate biomarkers of response of mammary tumors to tamoxifen and possibly to other selective estrogen receptor modulators (SERMs).
Christov
Konstantin
K
Department of Surgical Oncology, University of Illinois, Chicago, IL, USA. Christov@UIC.edu
Ikui
Amy
A
Shilkaitis
Anne
A
Green
Albert
A
Yao
Ruisheng
R
You
Ming
M
Grubbs
Clinton
C
Steele
Vernon
V
Lubet
Ronald
R
Weinstein
I Bernard
IB
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism*; D019927:Cyclin E / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008770:Methylnitrosourea; D009376:Neoplasms, Hormone-Dependent / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D014408:Biomarkers, Tumor; D019927:Cyclin E; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D019938:Cyclin D1; D008770:Methylnitrosourea