Rj. Daly et al., PROGRESSION TO STEROID AUTONOMY IS ACCOMPANIED BY ALTERED SENSITIVITYTO GROWTH-FACTORS IN S115 MOUSE MAMMARY-TUMOR CELLS, Journal of steroid biochemistry and molecular biology, 54(1-2), 1995, pp. 21-29
Progression to steroid autonomy is a major clinical problem in the tre
atment of steroid-sensitive tumours. Molecular mechanisms remain unkno
wn but recent hypotheses imply a role for growth factors in this progr
ession. Since S115 + A androgen-responsive mouse mammary tumour cells
provide a model system to study this phenomenon in vitro, we have used
this model to investigate growth factor gene expression and sensitivi
ty during progression from a steroid sensitive to insensitive state. S
115 + A androgen-responsive cells showed a positive proliferative resp
onse, morphological response and increased saturation density to vario
us forms of fibroblast growth factor (FGF) and transforming growth fac
tor beta (TGF beta) in both monolayer and suspension culture. A marked
synergy was noted, however, between FGF and TGF beta in promoting gro
wth in suspension culture. S115 + A cells possessed mRNA for both acid
ic FGF (aFGF) and TGF beta(1), both of which were increased by testost
erone. Progression to androgen insensitivity was associated with a rev
ersal of growth factor response such that all growth factor responses
became generally inhibitory on growth of the unresponsive cells but wi
th a particularly striking synergistic action between FGF and TGF beta
(1) on inhibition of both monolayer and suspension growth. Levels of a
FGF and TGF beta(1) mRNAs remained low in steroid-insensitive S115 - A
cells, indicating that loss of response was not associated with any c
onstitutive upregulation of endogenous production of one of these grow
th factors. The scientific and clinical implications are discussed.