title: ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression.
abstract: Expression of ADAM12 is low in most normal tissues but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In this study, we found that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 seems to be dispensable for its tumor-promoting effect. Interestingly, we show that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence tumor progression, but that ADAM12 expression by tumor cells is necessary for tumor progression in these mice. This finding is consistent with our observation that in human breast carcinoma, ADAM12 is almost exclusively located in tumor cells and, only rarely, seen in the tumor-associated stroma. We hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, on the basis of the fact that TGF-β1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-β1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12 synthesis, and growth of these cells in vivo induced more than 200-fold increase in ADAM12 expression. Our observation that ADAM12 expression is significantly higher in the terminal duct lobular units (TDLU) adjacent to human breast carcinoma compared with TDLUs found in normal breast tissue supports our hypothesis that tumor-associated stroma triggers ADAM12 expression.
authors.affiliation: Department of Biomedical Sciences and Biotech Research & Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N, Denmark. ullaw@sund.ku.dk
authors.forename: Camilla
authors.initials: C
authors.lastname: Fröhlich
authors.forename: Camilla
authors.initials: C
authors.lastname: Nehammer
authors.forename: Reidar
authors.initials: R
authors.lastname: Albrechtsen
authors.forename: Pauliina
authors.initials: P
authors.lastname: Kronqvist
authors.forename: Marie
authors.initials: M
authors.lastname: Kveiborg
authors.forename: Atsuko
authors.initials: A
authors.lastname: Sehara-Fujisawa
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Mercurio
authors.forename: Ulla M
authors.initials: UM
authors.lastname: Wewer
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000072199:ADAM12 Protein; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; C096115:Adam12 protein, mouse