Modulated expression of genes encoding estrogen metabolizing enzymes by G1-phase cyclin-dependent kinases 6 and 4 in human breast cancer cells.
G1-phase cell cycle defects, such as alterations in cyclin D1 or cyclin-dependent kinase (cdk) levels, are seen in most tumors. For example, increased cyclin D1 and decreased cdk6 levels are seen in many human breast tumors. Overexpression of cdk6 in breast tumor cells in culture has been shown to suppress proliferation, unlike the growth stimulating effects of its close homolog, cdk4. In addition to directly affecting proliferation, alterations in cdk6 or cdk4 levels in breast tumor cells also differentially influence levels of numerous steroid metabolic enzymes (SMEs), including those involved in estrogen metabolism. Overexpression of cdk6 in tumor cell lines having low cdk6 resulted in decreased levels of mRNAs encoding aldo-keto reductase (AKR)1C1, AKR1C2 and AKR1C3, which are hydroxysteroid dehydrogenases (HSDs) involved in steroid hormone metabolism. In contrast, increasing cdk4 dramatically increased these transcript levels, especially those encoding AKR1C3, an enzyme that converts estrone to 17β-estradiol, a change that could result in a pro-estrogenic state favoring tumor growth. Effects on other estrogen metabolizing enzymes, including cytochrome P450 (CYP) 19 aromatase, 17β-HSD2, and CYP1B1 transcripts, were also observed. Interactions of cdk6 and cdk4, but not cyclin D1, with the promoter region of a cdk-regulated gene, 17β-HSD2, were detected. The results uncover a previously unsuspected link between the cell cycle and hormone metabolism and differential roles for cdk6 and cdk4 in a novel mechanism for pre-receptor control of steroid hormone action, with important implications for the origin and treatment of steroid hormone-dependent cancers.
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America.
Yi
Y
Jia
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America.
Joanne
J
Domenico
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America.
Christina
C
Swasey
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America.
Meiqin
M
Wang
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America.
Erwin W
EW
Gelfand
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America.
Joseph J
JJ
Lucas
D015089:20-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics* / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D004960:Estradiol Dehydrogenases / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D004970:Estrone / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D015089:20-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001141:Aromatase; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D065633:Cytochrome P-450 CYP1B1; D004958:Estradiol; D004960:Estradiol Dehydrogenases; D004967:Estrogens; D004970:Estrone; D006911:Hydroxyprostaglandin Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C487341:AKR1C3 protein, human; C523763:HSD17B2 protein, human; C561410:CYP19A1 protein, human; C585496:CYP1B1 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human