Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression.
It has been proposed that the insulin-like growth factors (IGFs) can act as autocrine and/or paracrine growth promoters in breast cancer. To investigate this hypothesis, we infected early passage MCF-7 cells with a retroviral vector containing the coding sequence for the IGF-II preprohormone along with a constitutive cytomegalovirus promoter sequence. These cells do not normally express IGF-I or IGF-II. After infection with the retroviral vector, several single cell clones were analyzed. Seven of nine isolated clones expressed very high levels of IGF-II mRNA. Biologically active IGF-II protein was easily detectable in the medium conditioned by the IGF-II-expressing clones, and IGF receptors were down-regulated in these. All IGF-II-expressing clones showed marked morphological changes in anchorage-dependent culture, growing in large clumps and as free-floating colonies. The cells also cloned in soft agar in the absence of estrogen, while the wild-type MCF-7 cells and control cells infected with an irrelevant DNA sequence showed none of these properties. alpha IR-3, an antibody that blocks the type I IGF receptor, inhibited the growth of IGF-II-expressing clones in serum-free medium. This model demonstrates that IGF-II can serve as an autocrine growth stimulant in breast cancer epithelial cells and that IGF-II overexpression may be capable of mediating malignant progression in human breast cancer.
Cullen
K J
KJ
Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, D.C. 20007.
Lippman
M E
ME
Chow
D
D
Hill
S
S
Rosen
N
N
Zwiebel
J A
JA
D001943:Breast Neoplasms / Q000503:physiopathology; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D004967:Estrogens / Q000502:physiology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000502:physiology; D017451:Receptors, Somatomedin; D012190:Retroviridae / Q000235:genetics; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured
D004967:Estrogens; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D007335:Insulin-Like Growth Factor II