HBX causes cyclin D1 overexpression and development of breast cancer in transgenic animals that are heterozygous for p53.
Transgenic mice, which selectively express the WAP-HBX transgene in mammary gland epithelial cells (ME-cells), were established in order to elucidate the consequences of HBX gene expression on organ differentiation, cell death program and tumor development. Transgene expression was demonstrable by RT-PCR, Northern and Western blot analysis during pregnancy, lactation and after weaning. HBX synthesis neither affect mammary gland differentiation nor apoptosis in ME-cells. Although breast cancer formation was rare in WAP-HBX animals (<1%), WAP-HBX*p53+/- hybrid animals developed breast tumors at an increased rate (12/85) after a latency period of 8-18 months. We also show here for the first time that HBX can immortalize ME-cells generated from mammary gland tissue segments in a p53-independent fashion. HBX causes cyclin D1 gene overexpression during early pregnancy, and this is maintained in ME-cells isolated either from mammary gland or from breast tumors. Intranuclear cyclin D1 accumulation also occurs in the absence of external growth factors and the BrdU incorporation rate remains high under serum starvation conditions. Finally, both cyclin D1 induction and HBX mitotic activity are dependent on p38 and c-Jun N-terminal kinase, but not on MEK-1 kinase activity.
Klein
Andreas
A
Institut für Molekularbiologie und Biochemie, Freie Universität Berlin, Arnimallee 22, Berlin 14195, Germany.
Guhl
Eva
E
Tzeng
Yin-Jeh
YJ
Fuhrhop
Jutta
J
Levrero
Massimo
M
Graessmann
Monika
M
Graessmann
Adolf
A
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D008321:Mammary Glands, Animal / Q000473:pathology / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation; D054334:Viral Regulatory and Accessory Proteins
D056741:Cyclin D; D016213:Cyclins; D008894:Milk Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C024471:whey acidic proteins