Cyclin D1 overexpression in a model of human breast premalignancy: preferential stimulation of anchorage-independent but not anchorage-dependent growth is associated with increased cdk2 activity.
Cyclin D1 is frequently overexpressed in human breast ductal carcinoma in situ (DCIS) specimens, which confer a high risk for the development of infiltrating ductal carcinoma. If causally involved in the genesis of human breast malignancy, cyclin D1 may represent an interesting target for chemopreventive approaches, as it sits at the junction of many growth factor and hormonal pathways. We have used the MCF-10A human breast cell line, derived from a mastectomy containing a low risk premalignant lesion, as a model system. Three cyclin D1 transfectants exhibited physiologically relevant levels of transgene overexpression, but no coordinate overexpression of other cell cycle related genes. Proliferation assays, flow cytometry, and cdk enzymatic assays of anchorage-dependent proliferation indicated only a minimal and transient effect of cyclin D1. In contrast, cyclin D1 overexpression significantly stimulated anchorage-independent colonization in soft agar or methylcellulose, accompanied by greater Gl-S progression. The cdk4 activity of the control- and cyclin D1 transfectants in colonization assays was comparable, but the cdk2 activity was higher in the latter. Injection of control- and cyclin D1 transfected MCF-10A cells in matrigel into nude mice failed to produce tumors within 1.5 years. The data suggest that cyclin D1 overexpression is an early feature of breast neoplastic progression, and can contribute to cancer development through the promotion of colonization.
Zhou
Q
Q
Women's Cancers Section, Laboratory of Pathology, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
Wulfkuhle
J
J
Ouatas
T
T
Fukushima
P
P
Stetler-Stevenson
M
M
Miller
F R
FR
Steeg
P S
PS
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D042846:CDC2-CDC28 Kinases; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011230:Precancerous Conditions / Q000235:genetics* / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012307:Risk Factors; D015291:Transforming Growth Factors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C065911:transforming growth factor type e; D019938:Cyclin D1; D015291:Transforming Growth Factors; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases