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

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.