High Cks1 expression in transgenic and carcinogen-initiated mammary tumors is not always accompanied by reduction in p27Kip1.
Cks1 plays an essential role in SCFSkp2-mediated ubiquitination, and consequently turnover, of the cdk2 inhibitor and tumor supressor p27Kip1. High Cks1 expression is associated with aggressive breast tumors and correlates with low p27Kip1 levels in some cases, although it is also an independent prognostic marker for survival, and provides predictive information in addition to that provided by p27Kip1 alone. In this report we demonstrate that Cks1 protein and mRNA are elevated to very high levels in mammary tumors initiated by erbB2, c-myc and polyoma middle-T (PyMT) in transgenic mice, whereas Cks1 protein is hardly detectable in the normal mammary epithelium. Cks1 is also highly upregulated in rat mammary tumors initiated by methylnitrosourea (MNU). Despite high levels of Cks1 expression, p27Kip1 levels were not reduced, and were in fact slightly higher in mammary tumors initiated by erbB2, PyMT and MNU. In contrast mammary tumors from MMTV-c-myc mice did exhibit low p27Kip1 and higher levels of Skp2. Together, these data suggest that deregulated Cks1 expression might play roles in oncogene and carcinogen-initiated mammary tumorigenesis independent of p27Kip1 turnover in certain tumors. Stable overexpression of Cks1 in human breast carcinoma MCF-7 cells did not significantly reduce p27Kip1 expression, although it conferred resistance to Faslodex (ICI 182780)-mediated inhibition of colony outgrowth in these cells. In contrast, Cks1-depleted MCF-7 cells formed fewer colonies in estrogen-containing medium. Therefore, our studies also suggest that Cks1 levels regulate the responsiveness of ER+ breast cancers to estrogens and anti-estrogens.
Biochemistry and Molecular Biology Department, Drug Discovery Division, Southern Research Institute, Birmingham, AL 35255, USA.
Louise
L
Westbrook
Harish N
HN
Ramanathan
Tatyana
T
Isayeva
Anshu Roy
AR
Mittal
Zhican
Z
Qu
Michael D
MD
Johnson
Francis G
FG
Kern
Selvarangan
S
Ponnazhagan
Clinton J
CJ
Grubbs
Jaideep V
JV
Thottassery
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D042846:CDC2-CDC28 Kinases / Q000235:genetics* / Q000378:metabolism; D002273:Carcinogens; D002277:Carcinoma / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D008770:Methylnitrosourea; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D002273:Carcinogens; D004967:Estrogens; D011960:Receptors, Estrogen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077267:Fulvestrant; D004958:Estradiol; D008770:Methylnitrosourea; D042846:CDC2-CDC28 Kinases; C474110:Cks1 protein, mouse