A role for ADAM12 in breast tumor progression and stromal cell apoptosis.
As in developmental and regenerative processes, cell survival is of fundamental importance in cancer. Thus, a tremendous effort has been devoted to dissecting the molecular mechanisms involved in understanding the resistance of tumor cells to programmed cell death. Recently, the importance of stromal fibroblasts in tumor initiation and progression has been elucidated. Here, we show that stromal cell apoptosis occurs in human breast carcinoma but is only rarely seen in nonmalignant breast lesions. Furthermore, we show that ADAM12, a disintegrin and metalloprotease up-regulated in human breast cancer, accelerates tumor progression in a mouse breast cancer model. ADAM12 does not influence tumor cell proliferation but rather confers both decreased tumor cell apoptosis and increased stromal cell apoptosis. This dual role of ADAM12 in governing cell survival is underscored by the finding that ADAM12 increases the apoptotic sensitivity of nonneoplastic cells in vitro while rendering tumor cells more resistant to apoptosis. Together, these results show that the ability of ADAM12 to influence apoptosis may contribute to tumor progression.
Kveiborg
Marie
M
Institute of Molecular Pathology, University of Copenhagen, Denmark.
Fröhlich
Camilla
C
Albrechtsen
Reidar
R
Tischler
Verena
V
Dietrich
Nikolaj
N
Holck
Peter
P
Kronqvist
Pauliina
P
Rank
Fritz
F
Mercurio
Arthur M
AM
Wewer
Ulla M
UM
D041721:3T3-L1 Cells; D051722:ADAM Proteins; D000072199:ADAM12 Protein; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms / Q000473:pathology*; D016466:CHO Cells; D048708:Cell Growth Processes / Q000502:physiology; D006224:Cricetinae; D018450:Disease Progression; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D008666:Metalloendopeptidases / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D017154:Stromal Cells / Q000166:cytology
D008565:Membrane Proteins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; D008666:Metalloendopeptidases