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

Yukie Takabatake, Claus Oxvig, Chandandeep Nagi, Kerin Adelson, Shabnam Jaffer, Hank Schmidt, Patricia J. Keely, Kevin W. Eliceiri, John Mandeli, Doris Germain

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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 shortperiod 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
Pages (from-to)388-406
Number of pages19
JournalEMBO Molecular Medicine
Issue number4
StatePublished - 1 Apr 2016


  • Breastfeeding
  • IGF-binding protein 4 and 5
  • Insulin-like growth (IGF) factor signaling
  • Involution


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