title: Transforming growth factor-beta signaling helps specify tumor type in DMBA and hormone-induced mammary cancers.
abstract: To determine the role of transforming growth factor-beta (TGF-beta) signaling in mammary development and tumor formation, we previously generated transgenic mice that expressed a dominant-negative form of the TGF-beta type II receptor (DNIIR) under the control of DNA regulatory elements from the metallothionein promoter (MT-DNIIR-28). In this report, we tested the hypothesis that loss of TGF-beta signaling in the mammary gland alters the development of chemically or hormonally induced tumors in mice. Four groups of mice were used in the study: wild-type and MT-DNIIR-28 mice on zinc with pituitary isograft, and wild-type and MT-DNIIR-28 mice on zinc with pituitary isograft treated with the carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). Tumor-free survival over time, tumor growth rate, and tumor pathology were measured. Statistically significant differences in tumor free survival over time or tumor growth rate were not detected in wild-type versus transgenic mice treated with DMBA. In contrast, tumor-free survival was significantly altered in transgenic mice that were treated with the pituitary isograft alone with MT-DNIIR mice developing tumors more quickly. Alterations in the types of tumors that formed in wild-type versus MT-DNIIR DMBA-treated mice were detected. In wild-type mice, tumors with squamous differentiation or bicellular adenomyoepitheliomas were most common. Adenomyoepitheliomas were not detected in transgenic mice. Furthermore, there was reduced staining for alpha smooth muscle actin and keratin 14, markers for myoepithelial cells, in the glandular portion of tumors in transgenic mice. The pathology of tumors induced by pituitary isograft alone was also markedly different in wild-type and transgenic mice. All the tumors classified from wild-type mice demonstrated some form of squamous differentiation, whereas squamous differentiation was not detected in the pituitary-induced transgenic tumors. The results suggest that TGF-beta acts as a tumor suppressor for hormone-induced cancers and that TGF-beta has a role in determining tumor pathology by regulating myoepithelial or squamous differentiation, maintenance, or transformation.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham 1918 University Blvd, 310 MCLM Birmingham, AL 35294-0005, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Crowley
authors.forename: Andra
authors.initials: A
authors.lastname: Frost
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.forename: Michael O
authors.initials: MO
authors.lastname: Baffi
authors.forename: Teodora
authors.initials: T
authors.lastname: Nicola
authors.forename: Rosa
authors.initials: R
authors.lastname: Serra
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000473:pathology; D002454:Cell Differentiation; D005260:Female; D005799:Genes, Dominant; D015674:Mammary Neoplasms, Animal / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009208:Myoepithelioma / Q000209:etiology / Q000473:pathology; D010907:Pituitary Hormones / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D010907:Pituitary Hormones; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D015127:9,10-Dimethyl-1,2-benzanthracene; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II