Increased expression of dystroglycan inhibits the growth and tumorigenicity of human mammary epithelial cells.
Dystroglycan (DG) is an adhesion molecule formed by two subunits, alpha (extracellular) and beta (transmembrane) DG, which are codified by a single gene and form a continuous link from the extracellular matrix to the intracellular cytoskeleton. Reduction or loss of expression of DG has been observed in human cancer cell lines and primary tumors and has been suggested to promote tumor development and invasiveness. In this study, the human breast epithelial non-tumorigenic MCF10F and the breast cancer MCF7 cell lines were engineered to stably express an exogenous DG cDNA and the effects on the phenotype of both cell lines were evaluated. The MCF10F transfected cells displayed an increased expression of both DG subunits which was associated with inhibition of the anchorage-dependent growth, accumulation of cells in the G0/G1 phase of the cell cycle and increased adhesion to a substratum. The MCF7 transfected cells were unable to restore alpha-DG despite an increased expression of the beta-DG subunit. Anchorage-dependent and independent growth and the in vivo tumorigenicity were reduced in these derivatives that also displayed a reduced adhesion to a substratum and were shown to release alpha-DG in the culture medium. These findings confirm and extend previous evidence that transformation of mammary epithelial cells is associated with loss of their ability to retain alpha-DG on the cell membrane. Moreover, they indicate that DG is involved in cell functions other than cell adhesion to the extracellular matrix, and that its loss of function might predispose to tumor progression by compromising regulatory controls over cell growth and proliferation.
Sgambato
Alessandro
A
Centro di Ricerche Oncologiche Giovanni XXIII, Istituto di Patologia Generale, Catholic University, Rome, Italy. asgambato@rm.unicatt.it
Camerini
Andrea
A
Faraglia
Beatrice
B
Pavoni
Ernesto
E
Montanari
Micaela
M
Spada
Daniele
D
Losasso
Carmen
C
Brancaccio
Andrea
A
Cittadini
Achille
A
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002453:Cell Cycle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D049030:Dystroglycans / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D015870:Gene Expression / Q000502:physiology*; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014162:Transfection; D014407:Tumor Cells, Cultured
D049030:Dystroglycans