Novel tumor-promoting property of tamoxifen.
The tumor-promoting phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate) cooperates with c-Src overexpression to transform rat fibroblasts. TPA transforms c-Src-overexpressing cells by depleting the delta isoform of protein kinase C (PKCdelta). Tamoxifen, which has both estrogen-mimetic and estrogen-antagonist properties, has been widely used to improve the prognosis of breast cancer patients. However, with extended use, there is an increased risk for endometrial and other cancers that can be observed within 10 years of treatment. We report here that tamoxifen, similar to TPA, cooperates with c-Src overexpression to transform 3Y1 rat fibroblasts. Tamoxifen induced both DNA synthesis and anchorage-independent cell proliferation in c-Src-overexpressing, but not in parental, 3Y1 rat fibroblasts. Tamoxifen also induced an association between c-Src and PKCdelta that resulted in the tyrosine phosphorylation and down-regulation of PKCdelta. These phenotypes were not induced by estrogen, indicating that the effect of tamoxifen was in addition to any estrogen-mimetic effects. Thus, in addition to the hyperplasia-inducing capability of an estrogen-mimetic, tamoxifen has an additional tumor-promoting capability similar to that of TPA. The dual tumor-promoting capability of both estrogen- and TPA-mimetic properties for tamoxifen may contribute to the increased incidence of endometrial cancers observed in the relatively short exposure period of <10 years.
Zhong
M
M
Department of Biological Sciences, Hunter College of The City University of New York, New York, New York 10021, USA.
Lu
Z
Z
Abbas
T
T
Hornia
A
A
Chatakondu
K
K
Barile
N
N
Kaplan
P
P
Foster
D A
DA
D000818:Animals; D002273:Carcinogens / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D016889:Endometrial Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D045166:Estradiol Congeners / Q000009:adverse effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D016391:Genes, src / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051745:Protein Kinase C-delta; D051381:Rats; D013629:Tamoxifen / Q000009:adverse effects*; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects / Q000494:pharmacology
D002273:Carcinogens; D045166:Estradiol Congeners; D013629:Tamoxifen; C497260:Prkcd protein, rat; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate