Cloning and overexpression of TGF-beta 1 cDNA in a mammary adenocarcinoma: in vitro and in vivo effects.

It has been suggested that transforming growth factor beta (TGF-beta) may be a potential negative autocrine growth regulator of carcinomas including mammary carcinomas. To directly test this hypothesis we have cloned and expressed human TGF-beta 1 cDNA in a murine mammary adenocarcinoma which is normally growth-inhibited by addition of exogenous TGF-beta in vitro. A number of transfectants over-expressing the foreign TGF-beta 1 mRNA were selected and compared to transfectants which did not overexpress the exogenous TGF-beta 1 cDNAS. Cell lines overexpressing the transfected TGF-beta 1 mRNA were found to produce total levels of TGF-beta 7 to 10 fold greater than the parental cells or control transfected clones. However, when levels of active fractions of TGF-beta were compared in cell lines overexpressing TGF-beta 1 to those which did not, no differences were found. This suggests that the activation mechanism is not necessarily induced or altered by increasing levels of latent TGF-beta 1 production in a given tumor cell line. The basal in vitro doubling time of TGF-beta 1 overexpressing clones was identical to the control populations. Similarly, in vivo tumor growth rates after s.c. injection were similar to that of the parental line. Thus the precise role of TGF-beta in mediating either the in vitro or in vivo growth control of a sensitive mammary adenocarcinoma cell line remains unclear. It may be that cellular over-secretion of latent TGF-beta must be coupled with enhanced cellular TGF-beta activation prior to any observed effect on growth rate in vitro or in vivo; this latter event may constitute the "rate-limiting" step of TGF-beta activity on tumor behavior.