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Breast Cancer Research

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Open Access 01-12-2019 | Breast Cancer | Research article

Parity predisposes breasts to the oncogenic action of PAPP-A and activation of the collagen receptor DDR2

Authors: Elizabeth Slocum, Amanda Craig, Augusto Villanueva, Doris Germain

Published in: Breast Cancer Research | Issue 1/2019

Abstract

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.

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Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer. 2006;6(4):281–91. https://doi.org/10.1038/nrc1839.CrossRefPubMed

Cancer CG on HF in B. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet. 1997;350(9084):1047–59. https://doi.org/10.1016/S0140-6736(97)08233-0.CrossRef

Albrektsen G, Heuch I, Thoresen S. Histological type and grade of breast cancer tumors by parity, age at birth, and time since birth: a register-based study in Norway. BMC Cancer. 2010;10(1):226. https://doi.org/10.1186/1471-2407-10-226.CrossRefPubMedPubMedCentral

Callihan EB, Gao D, Jindal S, et al. Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer. Breast Cancer Res Treat. 2013;138(2):549–59. https://doi.org/10.1007/s10549-013-2437-x.CrossRefPubMedPubMedCentral

Lyons TR, Schedin PJ, Borges VF. Pregnancy and breast cancer : when they collide. J Mammary Gland Biol Neoplasia. 2009:87–98. https://doi.org/10.1007/s10911-009-9119-7.CrossRefPubMedPubMedCentral

Nichols HB, Schoemaker MJ, Cai J, et al. Breast cancer risk after recent childbirth a pooled analysis of 15 prospective studies. Ann Intern Med. 2018. https://doi.org/10.7326/M18-1323.CrossRefPubMedPubMedCentral

Andersson TM-L, Johansson ALV, Hsieh C-C, Cnattingius S, Lambe M. Increasing incidence of pregnancy-associated breast cancer in Sweden. Obstet Gynecol. 2009;114(3):568–72. https://doi.org/10.1097/AOG.0b013e3181b19154.CrossRefPubMed

Lyons TRTR, O’Brien J, Borges VFVF, et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med. 2011;17(9):1109–15. https://doi.org/10.1038/nm.2416.CrossRefPubMedPubMedCentral

Faupel-Badger JM, Arcaro KF, Balkam JJ, et al. Postpartum remodeling, lactation, and breast cancer risk: summary of a national cancer institute-sponsored workshop. J Natl Cancer Inst. 2013;105(3):166–74. https://doi.org/10.1093/jnci/djs505.CrossRefPubMed

10.

McDaniel SM, Rumer KK, Biroc SL, et al. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am J Pathol. 2006;168(2):608–20. https://doi.org/10.2353/ajpath.2006.050677.CrossRefPubMedPubMedCentral

11.

Ning Y, Hoang B, Schuller AGP, et al. Delayed mammary gland involution in mice with mutation of the insulin-like growth factor binding protein 5 gene. In: Endocrinology; 2013. https://doi.org/10.1210/en.2006-0041.

12.

Watson CJ, Kreuzaler PA. Remodeling mechanisms of the mammary gland during involution. Int J Dev Biol. 2011;55(7–9):757–62. https://doi.org/10.1387/ijdb.113414cw.CrossRefPubMed

13.

Conklin MW, Eickhoff JC, Riching KM, et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am J Pathol. 2011;178(3):1221–32. https://doi.org/10.1016/j.ajpath.2010.11.076.CrossRefPubMedPubMedCentral

14.

Maller O, Hansen KC, Lyons TR, et al. Collagen architecture in pregnancy-induced protection from breast cancer. J Cell Sci. 2013;126(Pt 18:4108–10. https://doi.org/10.1242/jcs.121590.CrossRefPubMedPubMedCentral

15.

Fang M, Yuan J, Peng C, Li Y. Collagen as a double-edged sword in tumor progression. Tumor Biol. 2014;35(169):2871–82. https://doi.org/10.1007/s13277-013-1511-7.CrossRef

16.

Luparello C. Aspects of collagen changes in breast cancer. Carcinog Mutagen. 2013;S13. https://doi.org/10.4172/2157-2518.S13-007.

17.

Provenzano PP, Inman DR, Eliceiri KW, et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 2008;6(11). https://doi.org/10.1186/1741-7015-6-11.

18.

Kakkad SM, Solaiyappan M, Argani P et al. Collagen I fiber density increases in lymph node positive breast cancers: pilot study. J Biomed Opt. 2012;17(11):116017. https://doi.org/10.1117/1.JBO.17.11.116017.CrossRefPubMedPubMedCentral

19.

Kuperwasser C. The tumor stromal microenvironment as modulator of malignant behavior. J Mammary Gland Biol Neoplasia. 2010;15:377–9. https://doi.org/10.1007/s10911-010-9198-5.CrossRefPubMed

20.

Mccready J, Sims JD, Chan D, Jay DG. Secretion of extracellular hsp90α via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer. 2010;10:294.CrossRefPubMedPubMedCentral

21.

Mansfield AS, Visscher DW, Hart SN, et al. Pregnancy-associated plasma protein-A expression in human breast cancer. Growth Hormon IGF Res. 2014;24(6):264–7. https://doi.org/10.1016/j.ghir.2014.10.007.CrossRef

22.

Takabatake Y, Oxvig C, Nagi C, et al. Lactation opposes pappalysin-1-driven pregnancy-associated breast cancer. EMBO Mol Med. 2016;8(4):388–406. https://doi.org/10.15252/emmm.201606273.CrossRefPubMedPubMedCentral

23.

Oxvig C. The role of PAPP-A in the IGF system: location, location, location. J Cell Commun Signal. 2015;9(2):177–87. https://doi.org/10.1007/s12079-015-0259-9.CrossRefPubMedPubMedCentral

24.

Overgaard MT, Bold HB, Laursen LS, Sottrup-Jensen L, Conover CA, Oxvig C. Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem. 2001;276(24):21849–53. https://doi.org/10.1074/jbc.M102191200.CrossRefPubMed

25.

Laursen LS, Overgaard MT, Soe R, et al. Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS Lett. 2001;504(1–2):36–40. https://doi.org/10.1016/S0014-5793(01)02760-0.CrossRefPubMed

26.

Ghoussaini M, Edwards SL, Michailidou K, et al. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nat Commun. 2014. https://doi.org/10.1038/ncomms5999.

27.

Kao K-J, Chang K-M, Hsu H-C, Huang AT. Correlation of microarray-based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization. BMC Cancer. 2011. https://doi.org/10.1186/1471-2407-11-143.

28.

Chanrion MI, Negre V, Grogan M, et al. A gene expression signature that can predict the recurrence of T reated primary breast cancer. Clin Cancer Res. 2008;14(3):1744–53. https://doi.org/10.1158/1078-0432.CCR-07-1833.CrossRefPubMedPubMedCentral

29.

Ritchie ME, Phipson B, Wu D, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015. https://doi.org/10.1093/nar/gkv007.CrossRefPubMedPubMedCentral

30.

Reich M, Tabor T, Liefeld T, et al. The GenePattern notebook environment. Cell Syst. 2017. https://doi.org/10.1016/j.cels.2017.07.003.CrossRefPubMedPubMedCentral

31.

Harrell FE. Regression modeling strategies. With applications to linear models, logistic regression, and survival analysis; 2001. https://doi.org/10.1007/978-1-4757-3462-1.CrossRef

32.

Guo Y, Bao Y, Guo D, Yang W. Pregnancy-associated plasma protein a in cancer: expression , oncogenic functions and regulation. Am J Cancer Res. 2018;8(6):955–63.PubMedPubMedCentral

33.

Chander H, Halpern M, Resnick-Silverman L, Manfredi JJ, Germain D. Skp2B overexpression alters a prohibitin-p53 axis and the transcription of PAPP-A, the protease of insulin-like growth factor binding protein 4. PLoS One. 2011. https://doi.org/10.1371/journal.pone.0022456.CrossRefPubMedPubMedCentral

34.

Conover CA. The IGF-p53 connection in cancer. Growth Hormon IGF Res. 2018. https://doi.org/10.1016/j.ghir.2017.11.007.CrossRef

35.

Schedin P, Keely PJ. Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb Perspect Biol. 2011;3(1):1–22. https://doi.org/10.1101/cshperspect.a003228.CrossRef

36.

Toy KA, Valiathan RR, Núñez F, et al. Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer. Breast Cancer Res Treat. 2015;150(1):9–18. https://doi.org/10.1007/s10549-015-3285-7.CrossRefPubMedPubMedCentral

37.

Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997;1(1):13–23. https://doi.org/10.1016/S1097-2765(00)80003-9.CrossRefPubMed

38.

Valiathan RR, Marco M, Leitinger B, Kleer CG, Fridman R. Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev. 2012;31(1–2):295–321. https://doi.org/10.1007/s10555-012-9346-z.CrossRefPubMedPubMedCentral

39.

Zhang K, Corsa CA, Ponik SM, et al. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol. 2013;15(6):677–87. https://doi.org/10.1038/ncb2743.CrossRefPubMedPubMedCentral

40.

Corsa CAS, Brenot A, Grither WR, et al. The action of discoidin domain receptor 2 in basal tumor cells and stromal cancer-associated fibroblasts is critical for breast cancer metastasis. Cell Rep. 2016;15(11):2510–23. https://doi.org/10.1016/j.celrep.2016.05.033.CrossRefPubMedPubMedCentral

41.

Gonzalez ME, Martin EE, Anwar T, Ge C. Mesenchymal stem cell-induced DDR2 mediates stromal-breast cancer interactions and metastasis article mesenchymal stem cell-induced DDR2 mediates stromal-breast cancer interactions and metastasis growth. Cell Rep. 2017;18(5):1215–28. https://doi.org/10.1016/j.celrep.2016.12.079.CrossRefPubMedPubMedCentral

42.

Smith BN, Burton LJ, Henderson V, et al. Snail promotes epithelial mesenchymal transition in breast cancer cells in part via activation of nuclear ERK2. PLoS One. 2014;9(8). https://doi.org/10.1371/journal.pone.0104987.CrossRefPubMedPubMedCentral

43.

Cano A, Pérez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83. https://doi.org/10.1038/35000025.CrossRefPubMed

44.

Luo WR, Li SY, Cai LM, Yao KT. High expression of nuclear Snail, but not cytoplasmic staining, predicts poor survival in nasopharyngeal carcinoma. Ann Surg Oncol. 2012. https://doi.org/10.1245/s10434-012-2347-x.CrossRefPubMed

45.

Muqbil I, Wu J, Aboukameel A, Mohammad RM, Azmi AS. Snail nuclear transport: the gateways regulating epithelial-to-mesenchymal transition? Semin Cancer Biol. 2014. https://doi.org/10.1016/j.semcancer.2014.06.003.CrossRefPubMedPubMedCentral

46.

Cai L, Fritz D, Stefanovic L, Stefanovic B. Binding of LARP6 to the conserved 5′ stem-loop regulates translation of mRNAs encoding type I collagen. J Mol Biol. 2010. https://doi.org/10.1016/j.jmb.2009.11.020.CrossRefPubMed

47.

Stefanovic L, Longo L, Zhang Y, Stefanovic B. Characterization of binding of LARP6 to the 5′ stem-loop of collagen mRNAs: implications for synthesis of type I collagen. RNA Biol. 2014. https://doi.org/10.1080/15476286.2014.996467.CrossRefPubMed

48.

Blackstock CD, Higashi Y, Sukhanov S, et al. Insulin-like growth factor-1 increases synthesis of collagen type I via induction of the mRNA-binding protein LARP6 expression and binding to the 5′ stem-loop of COL1a1 and COL1a2 mRNA. J Biol Chem. 2014. https://doi.org/10.1074/jbc.M113.518951.CrossRefPubMedPubMedCentral

49.

Zhang Y, Stefanovic B. Akt mediated phosphorylation of LARP6; critical step in biosynthesis of type I collagen. Sci Rep. 2016. https://doi.org/10.1038/srep22597.

50.

Bantscheff M, Eberhard D, Abraham Y, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007;25(9):1035–44. https://doi.org/10.1038/nbt1328.CrossRefPubMed

51.

Day E, Waters B, Spiegel K, et al. Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib. Eur J Pharmacol. 2008;599(1–3):44–53. https://doi.org/10.1016/j.ejphar.2008.10.014.CrossRefPubMed

52.

Mata R, Palladino C, Nicolosi ML, et al. IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget. 2016;7(7):7683–700. https://doi.org/10.18632/oncotarget.6524.CrossRefPubMed

53.

Becker MA, Haluska P, Bale LK, Oxvig C, Conover CA. A novel neutralizing antibody targeting pregnancy-associated plasma protein-a inhibits ovarian cancer growth and ascites accumulation in patient mouse tumorgrafts. Mol Cancer Ther. 2015. https://doi.org/10.1158/1535-7163.MCT-14-0880.CrossRefPubMedPubMedCentral

54.

Conover CA, Bale LK. Loss of pregnancy-associated plasma protein A extends lifespan in mice. Aging Cell. 2007. https://doi.org/10.1111/j.1474-9726.2007.00328.x.CrossRefPubMed

55.

González-Jiménez E, García PA, Aguilar MJ, Padilla CA, Álvarez J. Breastfeeding and the prevention of breast cancer: a retrospective review of clinical histories. J Clin Nurs. 2014. https://doi.org/10.1111/jocn.12368.CrossRefPubMed

56.

Jepsen MR, Kløverpris S, Mikkelsen JH, et al. Stanniocalcin-2 inhibits mammalian growth by proteolytic inhibition of the insulin-like growth factor axis. J Biol Chem. 2015. https://doi.org/10.1074/jbc.M114.611665.CrossRefPubMedPubMedCentral

57.

Kløverpris S, Mikkelsen JH, Pedersen JH, et al. Stanniocalcin-1 potently inhibits the proteolytic activity of the metalloproteinase pregnancy-associated plasma protein-A. J Biol Chem. 2015. https://doi.org/10.1074/jbc.M115.650143.CrossRefPubMedPubMedCentral

58.

Maskarinec G, Woolcott CG, Kolonel LN. Mammographic density as a predictor of breast cancer outcome. Future Oncol. 2010. https://doi.org/10.1186/bcr2654.

59.

Malaguarnera R, Nicolosi ML, Sacco A, et al. Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses. Oncotarget. 2015;6(18):16084–105. https://doi.org/10.18632/oncotarget.3177.CrossRefPubMedPubMedCentral

60.

Goddard ET, Bassale S, Schedin T, et al. Association between postpartum breast cancer diagnosis and metastasis and the clinical features underlying risk. 2019;2(1):1–15. https://doi.org/10.1001/jamanetworkopen.2018.6997.CrossRefPubMedPubMedCentral

61.

Guo F, Kuo YF, YCT S, Giordano SH, Berenson AB. Trends in breast cancer mortality by stage at diagnosis among young women in the United States. Breast Cancer Incid Mortal. 2018:3500–9. https://doi.org/10.1002/cncr.31638.CrossRefPubMed

62.

Turner N, Moretti E, Siclari O, et al. Cancer treatment reviews targeting triple negative breast cancer: is p53 the answer? Cancer Treat Rev. 2013;39(5):541–50. https://doi.org/10.1016/j.ctrv.2012.12.001.CrossRefPubMed

63.

Asztalos S, Pham TN, Gann PH, et al. High incidence of triple negative breast cancers following pregnancy and an associated gene expression signature. Springerplus. 2015;4:710. https://doi.org/10.1186/s40064-015-1512-7.CrossRefPubMedPubMedCentral

Title: Parity predisposes breasts to the oncogenic action of PAPP-A and activation of the collagen receptor DDR2
Authors: Elizabeth Slocum
Amanda Craig
Augusto Villanueva
Doris Germain
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Breast Cancer
Lactation
Breast Cancer
Published in: Breast Cancer Research / Issue 1/2019
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/s13058-019-1142-z

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