Transforming growth factor-alpha promotes mammary tumorigenesis through selective survival and growth of secretory epithelial cells.
Transforming growth factor (TGF)-alpha stimulates the growth and development of mammary epithelial cells and is implicated in the pathogenesis of human breast cancer. In this report we evaluate the consequences of overexpressing TGF-alpha in the mammary gland of transgenic mice and examine associated cellular mechanisms. When operating on a FVB/N genetic background (line MT100), TGF-alpha induced the stochastic development of mammary adenomas and adenocarcinomas f secretory epithelial origin in 64% of multiparous females. In contrast, tumors were exceedingly rare in virgin MT100 females, MT100 males, and multiparous FVB/N females. In MT100 females multiple foci of hyperplastic secretory lesions preceded the development of frank tumors; these initial lesions appeared during the involution period after the first lactation. Serial transplantation of these hyperplasias indicated an absence of proliferative immortality. Nevertheless, they gave rise to tumors at a low frequency and after a prolonged latency in virgin hosts; in multiparous hosts, tumors developed earlier and at a high incidence. The TGF-alpha transgene was highly expressed in hyperplasias and tumors but not in virgin and nonlesion-bearing tissue, suggesting that TGF-alpha overexpression provides a selective growth advantage. TGF-alpha also induced at lactation a 6.4-fold increase in DNA synthesis in MT100 epithelial cells, many of which were binucleated. MT100 mammary tissue experienced an obvious delay in involution, resulting in the postlactational survival of a significant population of unregressed secretory epithelial cells. In contrast, another line of transgenic mice on a CD-1 genetic background (MT42), in which TGF-alpha overexpression induced liver but not mammary tumors, failed to demonstrate postlactational epithelial cell survival. These data show that TGF-alpha promotes mammary tumorigenesis in multiparous MT100 mice by stimulating secretory epithelial cell proliferation during lactation and prolonging survival during involution. These points support the notion that TGF-alpha can act as a mitogen and also as a differentiation factor in mammary epithelium.
Smith
G H
GH
Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
Sharp
R
R
Kordon
E C
EC
Jhappan
C
C
Merlino
G
G
D000230:Adenocarcinoma / Q000209:etiology* / Q000473:pathology; D000236:Adenoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D004848:Epithelium / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D006965:Hyperplasia; D008321:Mammary Glands, Animal / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000473:pathology; D016378:Tissue Transplantation; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*
D016211:Transforming Growth Factor alpha