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

    Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

    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.

    OriginalsprogEngelsk
    TidsskriftEMBO Molecular Medicine
    Vol/bind8
    Nummer4
    Sider (fra-til)388-406
    Antal sider19
    ISSN1757-4676
    DOI
    StatusUdgivet - 2016

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