FIBROBLAST GROWTH FACTOR-IV TRANSFECTION OF MCF-7 CELLS PRODUCES CELL-LINES THAT ARE TUMORIGENIC AND METASTATIC IN OVARIECTOMIZED OR TAMOXIFEN-TREATED ATHYMIC NUDE-MICE

Successful antiestrogen treatment in patients with tamoxifen-responsiv e breast tumors is often followed by an outgrowth of tumors cells that are antiestrogen resistant, implying that estrogen-dependent tumors c an become estrogen-independent. In an effort to mimic this progression , we have transfected fibroblast growth factor 4 into MCF-7 cells, a h uman breast carcinoma cell line that is estrogen-dependent for growth in nude mice. This transfection results in cell lines that form progre ssively growing, metastatic tumors when injected s.c. into untreated o r tamoxifen-treated ovariectomized nude mice. In contrast to the paren tal cell line, growth of transfected cells in ovariectomized nude mice is stimulated by tamoxifen treatment and inhibited by estrogen treatm ent of the mice. Parental MCF-7 cells were transfected with an express ion vector for beta-galactosidase, conferring the ability to convert t he chromogenic substrate, 5-bromo-4-chloro-3-indoyl-beta-galactoside, to a blue color and allowing the detection of their presence within tu mors developing after coinoculation with fibroblast growth factor 4-tr ansfected cells. The fibroblast growth factor 4-transfected cells coul d support growth and metastasis of the beta-galactosidase-expressing p arental cell line when both lines were coinjected into the same site i n untreated or tamoxifen-treated, ovariectomized mice. These data sugg est a possible role for fibroblast growth factors in the progression o f breast tumors to an estrogen-independent, antiestrogen-resistant, me tastatic phenotype. They also support a role for paracrine factors in mixed populations of tumor cells of differing states of malignant prog ression.