Expression of Transforming Growth Factor α (TGFα) in Differentiated Rat Mammary Tumors: Estrogen Induction of TGFα Production

Abstract

Prmary well-differentiated dimethylbenzene .alpha.-anthracene (DMBA)-or nitrosomethylurea (NMU)-induced rat mammary adenocarcinomas that are estrogen dependent possess biologically active and immunoreactive transforming growth factor .alpha. (TGF.alpha.), which can be detected in a sort agar growth-promoting assay and by a specific liquid-phase competitive RIA, respectively. In contrast, tissue extracts prepared from transplantable undifferentiated DMBA-I and NMU-II rat mammary carcinomas that are estrogen independent and metastatic exhibit low or undetectable levels of TGF.alpha.. In addition, the primary DMBA- and NMU-induced rat mammary adenocarcinomas express a specific 4.8-kilobase TGF.alpha. mRNA species, whereas little or no TGF.alpha. mRNA can be detected in the transplantable DMBA-I and NMU-II tumors. Primary tumors synthesize type IV basement membrane collagen, whereas the transplantable tumors elaborate very little type IV collagen. Either TGF.alpha. or estrogens can differentially enhance the synthesis of type IV collagen by 0.5- to 4-fold over total protein synthesis in primary cultures of normal mouse mammary epithelial cells or in primary NMU-induced tumor cells, respectively. Therefore, TGF.alpha. could function as an estrogen-inducible autocrine growth factor for well differentiated rat mammary tumor cells by its ability to selectively regulate type IV collagen synthesis. Estrogens can modulate TGF.alpha. production in vivo in primary DMBA-induced rat mammary tumor, because ovariectomy results in a rapid decline (within 6 h) of TGF.alpha. mRNA levels. This response to estrogens can also be observed in vitro. Primary DMBA- or NMU-induced rat mammary tumor cells cultured in the presence of 17.beta.-estradiol (10-8 M) for 4 days show an increase in the level of TGF.alpha. mRNA over cells not treated with estrogen. This increase in TGF.alpha. mRNA is paralleled by a 2- to 3-fold increase in the levels of immunoreactive TGF.alpha. that can be detected and in the conditioned medium from estrogen-treated cells. These results suggest that TGF.alpha. may be an adjunct marker for those mammary tumors that are well differentiated adenocarcinomas and estrogen dependent and that estrogen-independent tumors do not constitutively produce TGF.alpha. or express TGF.alpha. mRNA.