title: Stromal matrix metalloproteinase-11 is involved in the mammary gland postnatal development.
abstract: MMP-11 is a bad prognosis paracrine factor in invasive breast cancers. However, its mammary physiological function remains largely unknown. In the present study we have investigated MMP-11 function during postnatal mammary gland development and function using MMP-11-deficient (MMP-11-/-) mice. Histological and immunohistochemical analyses as well as whole-mount mammary gland staining show alteration of the mammary gland in the absence of MMP-11, where ductal tree, alveolar structures and milk production are reduced. Moreover, a series of transplantation experiments allowed us to demonstrate that MMP-11 exerts an essential local paracrine function that favors mammary gland branching and epithelial cell outgrowth and invasion through adjacent connective tissues. Indeed, MMP-11-/- cleared fat pads are not permissive for wild-type epithelium development, whereas MMP-11-/- epithelium transplants grow normally when implanted in wild-type cleared fat pads. In addition, using primary mammary epithelial organoids, we show in vitro that this MMP-11 pro-branching effect is not direct, suggesting that MMP-11 acts via production/release of stroma-associated soluble factor(s). Finally, the lack of MMP-11 leads to decreased periductal collagen content, suggesting that MMP-11 has a role in collagen homeostasis. Thus, local stromal MMP-11 might also regulate mammary epithelial cell behavior mechanically by promoting extracellular matrix stiffness. Collectively, the present data indicate that MMP-11 is a paracrine factor involved during postnatal mammary gland morphogenesis, and support the concept that the stroma strongly impact epithelial cell behavior. Interestingly, stromal MMP-11 has previously been reported to favor malignant epithelial cell survival and promote cancer aggressiveness. Thus, MMP-11 has a paracrine function during mammary gland development that might be harnessed to promote tumor progression, exposing a new link between development and malignancy.
authors.affiliation: 1] Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France [2] Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: J
authors.initials: J
authors.lastname: Tan
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France.
authors.forename: E
authors.initials: E
authors.lastname: Buache
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France.
authors.forename: F
authors.initials: F
authors.lastname: Alpy
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France.
authors.forename: E
authors.initials: E
authors.lastname: Daguenet
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France.
authors.forename: C-L
authors.initials: CL
authors.lastname: Tomasetto
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: G-S
authors.initials: GS
authors.lastname: Ren
authors.affiliation: 1] Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Functional Genomics and Cancer, Centre National de la Recherche Scientifique UMR 7104, Institut National de la Santé et de la Recherche Médicale U964, Université de Strasbourg, Strasbourg, France [2] Equipe Labellisée Ligue National Contre le Cancer, Illkirch, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Rio
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development*; D053507:Matrix Metalloproteinase 11 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D019899:Paracrine Communication; D017154:Stromal Cells / Q000166:cytology*
chemical_list: D053507:Matrix Metalloproteinase 11