title: Progression to steroid autonomy is accompanied by altered sensitivity to growth factors in S115 mouse mammary tumour cells.
abstract: Progression to steroid autonomy is a major clinical problem in the treatment of steroid-sensitive tumours. Molecular mechanisms remain unknown but recent hypotheses imply a role for growth factors in this progression. 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 sensitivity during progression from a steroid sensitive to insensitive state. S115 + A androgen-responsive cells showed a positive proliferative response, morphological response and increased saturation density to various forms of fibroblast growth factor (FGF) and transforming growth factor beta (TGF beta) in both monolayer and suspension culture. A marked synergy was noted, however, between FGF and TGF beta in promoting growth in suspension culture. S115 + A cells possessed mRNA for both acidic FGF (aFGF) and TGF beta 1, both of which were increased by testosterone. Progression to androgen insensitivity was associated with a reversal of growth factor response such that all growth factor responses became generally inhibitory on growth of the unresponsive cells but with a particularly striking synergistic action between FGF and TGF beta 1 on inhibition of both monolayer and suspension growth. Levels of aFGF and TGF beta 1 mRNAs remained low in steroid-insensitive S115-A cells, indicating that loss of response was not associated with any constitutive upregulation of endogenous production of one of these growth factors. The scientific and clinical implications are discussed.
authors.affiliation: School of Animal and Microbial Sciences, University of Reading, Whiteknights, U.K.
authors.forename: R J
authors.initials: RJ
authors.lastname: Daly
authors.forename: N
authors.initials: N
authors.lastname: Carrick
authors.forename: P D
authors.initials: PD
authors.lastname: Darbre
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000494:pharmacology
chemical_list: D000728:Androgens; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors