title: Extracellular matrix regulates whey acidic protein gene expression by suppression of TGF-alpha in mouse mammary epithelial cells: studies in culture and in transgenic mice.
abstract: Whey acidic protein (WAP) is an abundant rodent milk protein. Its expression in mouse mammary epithelial cell cultures was previously found to require the formation of an extracellular matrix (ECM)-induced three-dimensional alveolar structure. In the absence of such structures, cells were shown to secrete diffusible factors leading to suppression of WAP expression. We demonstrate here that (a) TGF-alpha production and secretion by mammary cells is downregulated by the basement membrane-dependent alveolar structure, and (b) compared with beta-casein, WAP expression is preferentially inhibited both in culture and in transgenic mice when TGF-alpha is added or overexpressed. Thus, (c) the enhanced TGF-alpha production when cells are not in three-dimensional structures largely accounts for the WAP-inhibitory activity found in the conditioned medium. Since this activity can be abolished by incubating the conditioned medium with a function blocking antibody to TGF-alpha. The data suggest that ECM upregulates WAP by downregulating TGF-alpha production. We also propose that changes in TGF-alpha activity during mouse gestation and lactation could contribute to the pattern of temporal expression of WAP in the gland. These results provide a clear example of cooperation among lactogenic hormones, ECM, and locally acting growth factors in regulation of tissue-specific gene expression.
authors.affiliation: Life Science Division, Lawrence Berkeley Laboratories, Berkeley, California 94720, USA.
authors.forename: C Q
authors.initials: CQ
authors.lastname: Lin
authors.forename: P J
authors.initials: PJ
authors.lastname: Dempsey
authors.forename: R J
authors.initials: RJ
authors.lastname: Coffey
authors.forename: M J
authors.initials: MJ
authors.lastname: Bissell
mesh_terms: D000818:Animals; D002364:Caseins / Q000096:biosynthesis; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004847:Epithelial Cells; D004848:Epithelium / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology* / Q000648:ultrastructure; D005260:Female; D005786:Gene Expression Regulation; D007774:Lactation / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000096:biosynthesis*; D009500:Neutralization Tests; D011247:Pregnancy; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: D002364:Caseins; D017077:Culture Media, Conditioned; D008894:Milk Proteins; D016211:Transforming Growth Factor alpha; C024471:whey acidic proteins