The effects of a constitutive expression of transforming growth factor-alpha on the growth of MCF-7 human breast cancer cells in vitro and in vivo.
It has been suggested that transforming growth factor-alpha (TGF-alpha) is a mitogenic autocrine growth factor for human breast cancer cells, responsible for mediating the mitogenic effects of 17 beta-estradiol (E2) in responsive cells. To test this hypothesis we have introduced eukaryotic expression vectors directing the expression of TGF-alpha mRNA into E2-responsive MCF-7 human breast cancer cells. Transfected cells produce levels of TGF-alpha equivalent to or greater than those produced by both E2-stimulated MCF-7 cells and hormone-independent MDA-MB-231 cells. One transfected clone (H8) secretes sufficient TGF-alpha to fully down-regulate EGF-R expression. However, both of the transfected clones that constitutively secrete elevated levels of TGF-alpha (A8 and H8) respond to E2 stimulation in vitro by increasing the rate of cellular proliferation and inducing PGR synthesis. The basal proliferative capacity of H8 and A8 cells is equivalent to that of the parental cells and to cells transfected only with the G418 (neomycin) resistance gene. Furthermore, the TGF-alpha cDNA-transfected clones do not form tumors in ovariectomized athymic nude mice without E2 supplementation. Thus, the precise role of TGF-alpha in mediating either the in vivo or the in vitro mitogenic effects of E2 in MCF-7 human breast cancer cells remains unclear. While TGF-alpha expression may be essential, it is not sufficient alone to induce the fully E2-independent phenotype. Thus, TGF-alpha may function in combination with other E2-induced growth factors to control breast cancer proliferation and tumorigenesis.
Clarke
R
R
Medical Breast Cancer Section, National Cancer Institute, Bethesda, Maryland 20892.
Brünner
N
N
Katz
D
D
Glanz
P
P
Dickson
R B
RB
Lippman
M E
ME
Kern
F G
FG
D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D010957:Plasmids; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015291:Transforming Growth Factors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol; D015291:Transforming Growth Factors; D066246:ErbB Receptors