Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis.
Previous work has shown that cyclin D1 expression is required for neu- and ras-induced, but not wnt- or c-myc-induced, breast tumorigenesis in mice. Although cyclin D1 binds and activates cyclin-dependent kinase 4 (Cdk4), thereby mediating activation of a program of E2F-dependent gene expression, it has been suggested that the oncogenic activities of cyclin D1 are independent of Cdk4. To determine whether Cdk4 expression is required for breast tumorigenesis in mice, we have generated compound mice ectopically expressing the neu or wnt oncogenes in the mammary glands of wild-type and Cdk4-/- mice. Our results show that Cdk4 expression is required for efficient neu-induced tumorigenesis but is dispensable for wnt-induced breast tumorigenesis. In contrast to results previously observed in the mammary glands of cyclin D1-/- virgin females, our results show defects in mammary gland development in Cdk4-/- virgin females, suggesting differences in compensatory mechanisms in the absence of either subunit of the cyclin D1/Cdk4 complex. These results suggest that drugs targeted to inhibit Cdk4 activities could be developed to specifically treat certain breast tumors as Cdk4 is not essential for viability.
Reddy
Haritha K D L
HK
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Mettus
Richard V
RV
Rane
Sushil G
SG
Graña
Xavier
X
Litvin
Judith
J
Reddy
E Premkumar
EP
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology*; D008297:Male; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000254:growth & development; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D051155:Wnt1 Protein / Q000235:genetics
D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; C495893:Cdk2 protein, mouse; C495912:Cdk6 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6