Expression of a novel factor, com1, is regulated by 1,25-dihydroxyvitamin D-3 in breast cancer cells

Tumor cells and their surrounding microenviromment produce a variety of fac tors that promote tumor growth and metastasis, We recently identified a nuc lear factor, termed com1, that is up-regulated in human breast carcinoma ce lls on formation of experimental metastatic tumors and is assumed to act as a growth-promoting factor in breast cancer. 1,25-Dihydroxyvitamin D-3 [1,2 5(OH)(2)D-3] is a potent inhibitor of growth in breast cancer both in vitro and in vivo. We compared the growth-regulatory mechanisms of nontumorigeni c and estrogen-dependent MCF-7 cells with those of the tumorigenic and tamo xifen-resistant subline MCF7/LCC2 in the presence of 1,25(OH)(2)D-3. Prolif eration of MCF7/LCC2 cells, which revealed constitutive com1 expression, wa s inhibited by 1,25(OH)(2)D-3 (10(-7) M), This was strongly associated with cell cycle arrest in G(1) phase, consistent with accumulation of the hypop hosphorylated form of the retinoblastoma protein as well as the induction o f the cyclin-dependent kinase inhibitor p21, These cell cycle events were p receded by a transient up-regulation (5-8-fold) of com1 mRNA, Furthermore, clonal growth of the MCF7/LCC2 cells was also inhibited by 1,25(OH)(2)D-3 ( 10(-7) M), and when the com1-negative MCF-7 cells were stably transfected w ith com1, the resulting MCF7/com1 cells showed a significant decrease in co lony formation. These results seem to indicate that, rather than promoting growth, com1 may participate in the regulatory pathway involved in cellular growth inhibition when recruited by inhibitory signals.