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 PAP...
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| Format: | Article |
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Springer Nature
2016-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606273 |
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| author | Yukie Takabatake Claus Oxvig Chandandeep Nagi Kerin Adelson Shabnam Jaffer Hank Schmidt Patricia J Keely Kevin W Eliceiri John Mandeli Doris Germain |
| author_facet | Yukie Takabatake Claus Oxvig Chandandeep Nagi Kerin Adelson Shabnam Jaffer Hank Schmidt Patricia J Keely Kevin W Eliceiri John Mandeli Doris Germain |
| author_sort | Yukie Takabatake |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a3c1ba4b77a44936a9cd74d63af3b3d2 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a3c1ba4b77a44936a9cd74d63af3b3d22025-08-20T03:46:16ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-03-018438840610.15252/emmm.201606273Lactation opposes pappalysin‐1‐driven pregnancy‐associated breast cancerYukie Takabatake0Claus Oxvig1Chandandeep Nagi2Kerin Adelson3Shabnam Jaffer4Hank Schmidt5Patricia J Keely6Kevin W Eliceiri7John Mandeli8Doris Germain9Division of Hematology/Oncology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer InstituteDepartment of Molecular Biology and Genetics, Aarhus UniversityDepartment of Pathology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer InstituteDubin Breast Center of the Icahn School of Medicine, Tisch Cancer InstituteDepartment of Pathology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer InstituteDubin Breast Center of the Icahn School of Medicine, Tisch Cancer InstituteDepartment of Cell and Regenerative Biology, University of WisconsinLaboratory for Optical and Computational Instrumentation, University of WisconsinDepartment of Biostatistical Sciences, Icahn School of Medicine at Mount SinaiDivision of Hematology/Oncology of the Icahn School of Medicine at Mount Sinai, Tisch Cancer InstituteAbstract 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.https://doi.org/10.15252/emmm.201606273breastfeedingIGF‐binding protein 4 and 5insulin‐like growth (IGF) factor signalinginvolution |
| spellingShingle | Yukie Takabatake Claus Oxvig Chandandeep Nagi Kerin Adelson Shabnam Jaffer Hank Schmidt Patricia J Keely Kevin W Eliceiri John Mandeli Doris Germain Lactation opposes pappalysin‐1‐driven pregnancy‐associated breast cancer EMBO Molecular Medicine breastfeeding IGF‐binding protein 4 and 5 insulin‐like growth (IGF) factor signaling involution |
| title | Lactation opposes pappalysin‐1‐driven pregnancy‐associated breast cancer |
| title_full | Lactation opposes pappalysin‐1‐driven pregnancy‐associated breast cancer |
| title_fullStr | Lactation opposes pappalysin‐1‐driven pregnancy‐associated breast cancer |
| title_full_unstemmed | Lactation opposes pappalysin‐1‐driven pregnancy‐associated breast cancer |
| title_short | Lactation opposes pappalysin‐1‐driven pregnancy‐associated breast cancer |
| title_sort | lactation opposes pappalysin 1 driven pregnancy associated breast cancer |
| topic | breastfeeding IGF‐binding protein 4 and 5 insulin‐like growth (IGF) factor signaling involution |
| url | https://doi.org/10.15252/emmm.201606273 |
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