Parity predisposes breasts to the oncogenic action of PAPP-A and activation of the collagen receptor DDR2
| Autor: | Augusto Villanueva, Amanda J. Craig, Doris Germain, Elizabeth Slocum |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
LARP6
Involution Breast Neoplasms Mice Transgenic Disease Pregnancy-associated breast cancer lcsh:RC254-282 Metastasis Collagen receptor 03 medical and health sciences Mice 0302 clinical medicine Breast cancer Discoidin Domain Receptor 2 Surgical oncology Pregnancy Cell Line Tumor Medicine Animals Humans Pregnancy-Associated Plasma Protein-A DDR2 Involution (medicine) Neoplasm Metastasis TACS Oncogene business.industry Pregnancy-associated plasma protein A medicine.disease Prognosis lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immunohistochemistry 3. Good health Disease Models Animal Parity Cell Transformation Neoplastic Gene Expression Regulation 030220 oncology & carcinogenesis Cancer research Female Collagen Snail Family Transcription Factors business Insulin-like growth factor (IGF) signaling Research Article Signal Transduction |
| Zdroj: | Breast Cancer Research, Vol 21, Iss 1, Pp 1-20 (2019) Breast Cancer Research : BCR |
| DOI: | 10.1186/s13058-019-1142-z |
| Popis: | Background Women who had children at a young age (less than 25) show a reduced overall risk of breast cancer. However, epidemiological studies showed that for all other women, pregnancy increases the risk of breast cancer and the risk remains higher for decades. Further, even in women who had children at a young age, there is a transient increase risk that peaks 6 years after pregnancy. Women diagnosed with breast cancer following pregnancy show a higher rate of metastasis. Yet, the factors that increase the predisposition of post-partum breasts to more aggressive cancers remain unknown. Pregnancy-associated plasma protein A (PAPP-A) is a secreted protease that is overexpressed in more than 70% of breast cancers. However, PAPP-A is a collagen-dependent oncogene. We initiated this study to test the effect of PAPP-A on the predisposition of post-partum breasts. Methods We used PAPP-A mouse models for the analysis of its effect on virgin, involuting, or post-partum mammary glands. We performed second-harmonic generation microscopy for the analysis of collagen, defined tumor-associated collagen signature (TACS), the rate of mammary tumors, and the status of the collagen-DDR2-Snail axis of metastasis. We knockdown DDR2 by CRISPR and performed invasion assays. A transcriptomic approach was used to define a PAPP-A and parity-dependent genetic signature and assess its correlation with breast cancer recurrence in humans. Results We confirmed that post-partum mammary glands have a higher level of collagen than virgin glands and that this collagen is characterized by an anti-proliferative architecture. However, PAPP-A converts the anti-proliferative post-partum collagen into pro-tumorigenic collagen. We show that PAPP-A activates the collagen receptor DDR2 and metastasis. Further, deletion of DDR2 by CRISPR abolished the effect of PAPP-A on invasion. We defined a PAPP-A-driven genetic signature that identifies patients at higher risk of metastasis. Conclusions These results support the notion that information about pregnancy may be critical in the prognosis of breast cancer as passage through a single pregnancy predisposes to the oncogenic action of PAPP-A. Our data indicate that history of pregnancy combined with the expression of PAPP-A-driven genetic signature may be useful to identify patients at higher risk of metastatic disease. Electronic supplementary material The online version of this article (10.1186/s13058-019-1142-z) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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