Bax regulates c-Myc-induced mammary tumour apoptosis but not proliferation in MMTV-c-myc transgenic mice.
The expression of the proto-oncogene c-myc is frequently deregulated, via multiple mechanisms, in human breast cancers. Deregulated expression of c-myc contributes to mammary epithelial cell transformation and is causally involved in mammary tumorigenesis in MMTV-c-myc transgenic mice. c-Myc is known to promote cellular proliferation, apoptosis, genomic instability and tumorigenesis in several distinct tissues, both in vivo and in vitro. Expression of the proapoptotic regulatory gene bax is reduced or absent in human breast cancers, and c-Myc has been shown to regulate the expression of Bax, as well as cooperate with Bax in controlling apoptosis in a fibroblast model. Additionally, loss of bax reduces c-Myc-induced apoptosis in lymphoid cells and increases c-Myc-mediated lymphomagenesis in vivo. In order to assess whether loss of bax could influence c-Myc-induced apoptosis and tumorigenesis in the mammary gland in vivo, we generated MMTV-c-myc transgenic mice in which neither, one, or both wild-type alleles of bax were eliminated. Haploid loss of bax in MMTV-c-myc transgenic mice resulted in significantly reduced mammary tumour apoptosis. As anticipated for an apoptosis-regulatory gene, loss of the wild-type bax alleles did not significantly alter cellular proliferation in either mammary adenocarcinomas or dysplastic mammary tissues. However, in contrast to c-Myc-mediated lymphomagenesis, loss of one or both alleles of bax in MMTV-c-myc transgenic mice did not significantly enhance mammary tumorigenesis, despite evidence that haploid loss of bax might modestly increase mammary tumour multiplicity. Our results demonstrate that Bax contributes significantly to c-Myc-induced apoptosis in mammary tumours. In addition, they suggest that in contrast to c-Myc-induced lymphomagenesis, mammary tumorigenesis induced by deregulated c-myc expression requires some amount of Bax expression.
Jamerson
M H
MH
Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, DC 20057, USA.
Johnson
M D
MD
Korsmeyer
S J
SJ
Furth
P A
PA
Dickson
R B
RB
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D002455:Cell Division / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D015536:Down-Regulation; D016259:Genes, myc; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000503:physiopathology*; D008565:Membrane Proteins / Q000235:genetics* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2; D011991:Receptors, Virus / Q000235:genetics*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; C111417:Fam89b protein, mouse; C000715470:MAS1 protein, human; D008565:Membrane Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011991:Receptors, Virus; D051028:bcl-2-Associated X Protein