Expression of transforming growth factor α (TGFα) in differentiated rat mammary tumors: Estrogen induction of TGFα production

Abstract

Primary well-differentiated dimethylbenzene α-an-thracene (DMBA)-or nitrosomethylurea (NMU)-in- duced rat mammary adenocarcinomas that are estrogen dependent possess biologically active and immunoreactive transforming growth factor α (TGFα), 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 TGFα. In addition, the primary DMBA- and NMU-induced rat mammary adenocarcinomas express a specific 4.8-kilobase TGFα mRNA species, whereas little or no TGFα mRNA can be detected in the transplantable DMBAI and NMU-II tumors. Primary tumors synthesize type IV basement membrane collagen, whereas the transplantable tumors elaborate very little type IV collagen. Either TGFα 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, TGFα 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 TGFα production in vivo in primary DMBA-induced rat mammary tumors, because ovariectomy results in a rapid decline (within 6 h) of TGFα 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 17β-estradiol (10-8 M) for 4 days show an increase in the level of TGFα mRNA over cells not treated with estrogen. This increase in TGFα mRNA is paralleled by a 2- to 3-fold increase in the levels of immunoreactive TGFα that can be detected and in the conditioned medium from estrogen-treated cells. These results suggest that TGFα 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 TGFα or express TGFα Mrna. © 1987 by The Endocrine Society.