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Claus Oxvig

Lactation opposes pappalysin-1-driven pregnancy-associated breast cancer

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DOI

  • Yukie Takabatake, Division of Hematology/Oncology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
  • ,
  • Claus Oxvig
  • Chandandeep Nagi, Department of Pathology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
  • ,
  • Kerin Adelson, Dubin Breast Center of the Icahn School of Medicine, Tisch Cancer Institute, New York, NY, USA.
  • ,
  • Shabnam Jaffer, Department of Pathology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
  • ,
  • Hank Schmidt, Dubin Breast Center of the Icahn School of Medicine, Tisch Cancer Institute, New York, NY, USA.
  • ,
  • Patricia J Keely, Department of Cell and Regenerative Biology, University of Wisconsin, Madison, WI, USA.
  • ,
  • Kevin W Eliceiri, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, WI, USA.
  • ,
  • John Mandeli, Department of Biostatistical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • ,
  • Doris Germain, Division of Hematology/Oncology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA doris.germain@mssm.edu.

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.

Original languageEnglish
JournalEMBO Molecular Medicine
Volume8
Issue4
Pages (from-to)388-406
Number of pages19
ISSN1757-4676
DOIs
Publication statusPublished - 2016

    Research areas

  • Journal Article

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