title: Lactation opposes pappalysin-1-driven pregnancy-associated breast cancer.
abstract: Pregnancy is associated with a transient increase in risk for breast cancer. However, the mechanism underlying pregnancy-associated breast cancer (PABC) is poorly understood. Here, we identify the protease pappalysin-1 (PAPP-A) as a pregnancy-dependent oncogene. Transgenic expression of PAPP-A in the mouse mammary gland during pregnancy and involution promotes the deposition of collagen. We demonstrate that collagen facilitates the proteolysis of IGFBP-4 and IGFBP-5 by PAPP-A, resulting in increased proliferative signaling during gestation and a delayed involution. However, while studying the effect of lactation, we found that although PAPP-A transgenic mice lactating for an extended period of time do not develop mammary tumors, those that lactate for a short period develop mammary tumors characterized by a tumor-associated collagen signature (TACS-3). Mechanistically, we found that the protective effect of lactation is associated with the expression of inhibitors of PAPP-A, STC1, and STC2. Collectively, these results identify PAPP-A as a pregnancy-dependent oncogene while also showing that extended lactation is protective against PAPP-A-mediated carcinogenesis. Our results offer the first mechanism that explains the link between breast cancer, pregnancy, and breastfeeding.
authors.affiliation: Division of Hematology/Oncology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Takabatake
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Oxvig
authors.affiliation: Department of Pathology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
authors.forename: Chandandeep
authors.initials: C
authors.lastname: Nagi
authors.affiliation: Dubin Breast Center of the Icahn School of Medicine, Tisch Cancer Institute, New York, NY, USA.
authors.forename: Kerin
authors.initials: K
authors.lastname: Adelson
authors.affiliation: Department of Pathology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Jaffer
authors.affiliation: Dubin Breast Center of the Icahn School of Medicine, Tisch Cancer Institute, New York, NY, USA.
authors.forename: Hank
authors.initials: H
authors.lastname: Schmidt
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, USA.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
authors.affiliation: Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, WI, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Department of Biostatistical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Mandeli
authors.affiliation: Division of Hematology/Oncology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA doris.germain@mssm.edu.
authors.forename: Doris
authors.initials: D
authors.lastname: Germain
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007774:Lactation; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*
chemical_list: D011266:Pregnancy-Associated Plasma Protein-A; C579283:PAPPA protein, human
keywords: IGF‐binding protein 4 and 5; breastfeeding; insulin‐like growth (IGF) factor signaling; involution