PMID- 10882298 OWN - NLM STAT- MEDLINE DCOM- 20000714 LR - 20191104 IS - 1083-3021 (Print) IS - 1083-3021 (Linking) VI - 2 IP - 2 DP - 1997 Apr TI - Transgenic mice reveal roles for TGFalpha and EGF receptor in mammary gland development and neoplasia. PG - 119-29 AB - Transforming growth factor-alpha (TGFalpha)4 and/or the EGF receptor (EGFR) are frequently overexpressed by human and rodent breast tumors, as well as tumor-derived cell lines. Additionally, various observations suggest a role for TGFalpha and the EGFR signaling system in normal mouse mammary gland development. Recently, several laboratories have established TGFalpha transgenic mice with which to study the role of this growth factor in normal and neoplastic mammary biology. Examination of these mice revealed that overexpression of TGFalpha has profound consequences for this tissue. Most strikingly, transgenic mice expressing TGFalpha under the control of tissue-specific and nonspecific promoters stochastically developed focal mammary tumors with an incidence and latency that was markedly affected by pregnancy. Most TGFalpha-induced tumors were well-differentiated adenomas/adenocarcinomas, although some were undifferentiated and locally invasive. Distant metastases were only occasionally observed. Administration of the genotoxic carcinogen, 7,12-dimethylbenzanthracene (DMBA), dramatically accelerated mammary tumorigenesis induced by the TGFalpha transgene, raising the possibility that TGFalpha acts as a promoter in this tissue. Mice harboring dual transgenes encoding TGFalpha and either wild-type ERBB2 or c-myc displayed markedly accelerated tumorigenesis compared to mice carrying any of the single transgenes alone, indicative of potent cooperativity. Moreover, tumorigenesis in the bitransgenic mice was less dependent on pregnancy, and tumors were generally more malignant in appearance. Finally, TGFalpha also affected mammary gland dynamics. TGFalpha transgenic mice consistently displayed precocious alveolar development, were variably impaired with respect to lactation, and showed markedly reduced postlactional involution. As a result, the glands of multiparous females accumulated hyperplastic lesions that generally resembled milk-producing alveoli. Limited data support the hypothesis that these lesions were precursors to TGFalpha-induced tumors. In summary, these various findings underscore the potential importance of TGFalpha for cellular differentiation and transformation in the mammary gland. They also establish TGFalpha transgenic mice as a powerful model with which to study the role of EGFR signaling molecules in this dynamic tissue. FAU - Schroeder, J A AU - Schroeder JA AD - Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 27599-7295, USA. FAU - Lee, D C AU - Lee DC LA - eng GR - CA61896/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PT - Review PL - United States TA - J Mammary Gland Biol Neoplasia JT - Journal of mammary gland biology and neoplasia JID - 9601804 RN - 0 (Transforming Growth Factor alpha) RN - 57-97-6 (9,10-Dimethyl-1,2-benzanthracene) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - 9,10-Dimethyl-1,2-benzanthracene MH - Animals MH - Breast Neoplasms MH - *Cell Transformation, Neoplastic MH - ErbB Receptors/*physiology MH - Female MH - Humans MH - Mammary Glands, Animal/*physiology MH - Mammary Neoplasms, Experimental/chemically induced/genetics/*physiopathology MH - Mice MH - Mice, Transgenic MH - Pregnancy MH - Transforming Growth Factor alpha/genetics/*physiology RF - 64 EDAT- 1997/04/01 00:00 MHDA- 2000/07/25 11:00 CRDT- 1997/04/01 00:00 PHST- 1997/04/01 00:00 [pubmed] PHST- 2000/07/25 11:00 [medline] PHST- 1997/04/01 00:00 [entrez] AID - 10.1023/a:1026347629876 [doi] PST - ppublish SO - J Mammary Gland Biol Neoplasia. 1997 Apr;2(2):119-29. doi: 10.1023/a:1026347629876.