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Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2

Nature Medicine volume 17, pages 1109–1115 (2011)Cite this article

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Abstract

The prognosis of breast cancer in young women is influenced by reproductive history. Women diagnosed within 5 years postpartum have worse prognosis than nulliparous women or women diagnosed during pregnancy. Here we describe a mouse model of postpartum breast cancer that identifies mammary gland involution as a driving force of tumor progression. In this model, human breast cancer cells exposed to the involuting mammary microenvironment form large tumors that are characterized by abundant fibrillar collagen, high cyclooxygenase-2 (COX-2) expression and an invasive phenotype. In culture, tumor cells are invasive in a fibrillar collagen and COX-2–dependent manner. In the involuting mammary gland, inhibition of COX-2 reduces the collagen fibrillogenesis associated with involution, as well as tumor growth and tumor cell infiltration to the lung. These data support further research to determine whether women at high risk for postpartum breast cancer would benefit from treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) during postpartum involution.

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Figure 1: The postpartum mammary microenvironment promotes tumor growth in a mammary fat pad xenograft model.
Figure 2: Postpartum involution drives tumor cell invasion.
Figure 3: Fibrillar collagen and COX-2 mediate tumor cell invasiveness.
Figure 4: COX-2 inhibition mitigates the tumor-promotional effects of involution.
Figure 5: Evidence that collagen and COX-2 contribute to postpartum breast cancer.
Figure 6: Postpartum ibuprofen treatment reduces tumor volume, burden, COX-2 expression and lung infiltration.

References

  1. Lord, S.J. et al. Breast cancer risk and hormone receptor status in older women by parity, age of first birth, and breastfeeding: a case-control study. Cancer Epidemiol. Biomarkers Prev. 17, 1723–1730 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lambe, M. et al. Transient increase in the risk of breast cancer after giving birth. N. Engl. J. Med. 331, 5–9 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Mathews, T.J. & Hamilton, B.E. Delayed Childbearing: More Women are Having their First Child Later in Life Vol. 21 (National Center for Health Statistics, Hyattsville, MD, 2009).

  4. Lyons, T.R., Schedin, P.J. & Borges, V.F. Pregnancy and breast cancer: when they collide. J. Mammary Gland Biol. Neoplasia 14, 87–98 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Daling, J.R., Malone, K.E., Doody, D.R., Anderson, B.O. & Porter, P.L. The relation of reproductive factors to mortality from breast cancer. Cancer Epidemiol. Biomarkers Prev. 11, 235–241 (2002).

    PubMed  Google Scholar 

  6. Whiteman, M.K. et al. Reproductive history and mortality after breast cancer diagnosis. Obstet. Gynecol. 104, 146–154 (2004).

    Article  PubMed  Google Scholar 

  7. Dodds, L. et al. Relationship of time since childbirth and other pregnancy factors to premenopausal breast cancer prognosis. Obstet. Gynecol. 111, 1167–1173 (2008).

    Article  PubMed  Google Scholar 

  8. Stensheim, H., Moller, B., van Dijk, T. & Fossa, S.D. Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J. Clin. Oncol. 27, 45–51 (2009).

    Article  PubMed  Google Scholar 

  9. Bemis, L.T. & Schedin, P. Reproductive state of rat mammary gland stroma modulates human breast cancer cell migration and invasion. Cancer Res. 60, 3414–3418 (2000).

    CAS  PubMed  Google Scholar 

  10. Schedin, P., Mitrenga, T., McDaniel, S. & Kaeck, M. Mammary ECM composition and function are altered by reproductive state. Mol. Carcinog. 41, 207–220 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Clarkson, R.W., Wayland, M.T., Lee, J., Freeman, T. & Watson, C.J. Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Res. 6, R92–R109 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Stein, T. et al. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res. 6, R75–R91 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. McDaniel, S.M. et al. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am. J. Pathol. 168, 608–620 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. O'Brien, J. et al. Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. Am. J. Pathol. 176, 1241–1255 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schäfer, M. & Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nat. Rev. Mol. Cell Biol. 9, 628–638 (2008).

    Article  PubMed  Google Scholar 

  16. Coussens, L.M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schedin, P. Pregnancy-associated breast cancer and metastasis. Nat. Rev. Cancer 6, 281–291 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Wang, W. et al. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 62, 6278–6288 (2002).

    CAS  PubMed  Google Scholar 

  19. Butcher, D.T., Alliston, T. & Weaver, V.M. A tense situation: forcing tumour progression. Nat. Rev. Cancer 9, 108–122 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Paszek, M.J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Provenzano, P.P. et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 6, 11 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Broom, O.J., Massoumi, R. & Sjolander, A. α2β1 integrin signalling enhances cyclooxygenase-2 expression in intestinal epithelial cells. J. Cell Physiol. 209, 950–958 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Mann, J.R., Backlund, M.G. & DuBois, R.N. Mechanisms of disease: inflammatory mediators and cancer prevention. Nat. Clin. Pract. Oncol. 2, 202–210 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Thun, M.J., Namboodiri, M.M. & Heath, C.W. Jr. Aspirin use and reduced risk of fatal colon cancer. N. Engl. J. Med. 325, 1593–1596 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Elder, D.J. & Paraskeva, C. COX-2 inhibitors for colorectal cancer. Nat. Med. 4, 392–393 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Sheehan, K.M. et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. J. Am. Med. Assoc. 282, 1254–1257 (1999).

    Article  CAS  Google Scholar 

  27. Ristimäki, A. et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res. 62, 632–635 (2002).

    PubMed  Google Scholar 

  28. Denkert, C. et al. Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma. Cancer 97, 2978–2987 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Spizzo, G. et al. Correlation of COX-2 and Ep-CAM overexpression in human invasive breast cancer and its impact on survival. Br. J. Cancer 88, 574–578 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Howe, L.R. Inflammation and breast cancer. Cyclooxygenase/prostaglandin signaling and breast cancer. Breast Cancer Res. 9, 210 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Minn, A.J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bos, P.D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gauthier, M.L. et al. Abrogated response to cellular stress identifies DCIS associated with subsequent tumor events and defines basal-like breast tumors. Cancer Cell 12, 479–491 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Visscher, D.W. et al. Association between cyclooxygenase-2 expression in atypical hyperplasia and risk of breast cancer. J. Natl. Cancer Inst. 100, 421–427 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Kwan, M.L., Habel, L.A., Slattery, M.L. & Caan, B. NSAIDs and breast cancer recurrence in a prospective cohort study. Cancer Causes Control 18, 613–620 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Holmes, M.D. et al. Aspirin intake and survival after breast cancer. J. Clin. Oncol. 28, 1467–1472 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu, C.H. et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J. Biol. Chem. 276, 18563–18569 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Howe, L.R. et al. HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. Cancer Res. 65, 10113–10119 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Larkins, T.L., Nowell, M., Singh, S. & Sanford, G.L. Inhibition of cyclooxygenase-2 decreases breast cancer cell motility, invasion and matrix metalloproteinase expression. BMC Cancer 6, 181 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Singh, B. et al. COX-2 involvement in breast cancer metastasis to bone. Oncogene 26, 3789–3796 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Miller, F.R., Santner, S.J., Tait, L. & Dawson, P.J. MCF10DCIS.com xenograft model of human comedo ductal carcinoma in situ. J. Natl. Cancer Inst. 92, 1185–1186 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Hu, M. et al. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell 13, 394–406 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Allred, D.C. et al. Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution. Clin. Cancer Res. 14, 370–378 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Sørlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 98, 10869–10874 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  45. van de Vijver, M.J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Provenzano, P.P. et al. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 4, 38 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Anders, C.K. et al. Breast carcinomas arising at a young age: unique biology or a surrogate for aggressive intrinsic subtypes? J. Clin. Oncol. 29, e18–e20 (2011).

    Article  PubMed  Google Scholar 

  48. Chang, H.Y. et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc. Natl. Acad. Sci. USA 102, 3738–3743 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rodriguez, A.O. et al. Evidence of poorer survival in pregnancy-associated breast cancer. Obstet. Gynecol. 112, 71–78 (2008).

    Article  PubMed  Google Scholar 

  50. Lethaby, A.E., O'Neill, M.A., Mason, B.H., Holdaway, I.M. & Harvey, V.J. Overall survival from breast cancer in women pregnant or lactating at or after diagnosis. Auckland Breast Cancer Study Group. Int. J. Cancer 67, 751–755 (1996).

    Article  CAS  PubMed  Google Scholar 

  51. Bladström, A., Anderson, H. & Olsson, H. Worse survival in breast cancer among women with recent childbirth: results from a Swedish population-based register study. Clin. Breast Cancer 4, 280–285 (2003).

    Article  PubMed  Google Scholar 

  52. Gupta, P.B. et al. Systemic stromal effects of estrogen promote the growth of estrogen receptor-negative cancers. Cancer Res. 67, 2062–2071 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Levental, K.R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wilgus, T.A. et al. The impact of cyclooxygenase-2 mediated inflammation on scarless fetal wound healing. Am. J. Pathol. 165, 753–761 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Conklin, M.W. et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Howe, L.R. et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res. 62, 5405–5407 (2002).

    CAS  PubMed  Google Scholar 

  57. Krause, S., Maffini, M.V., Soto, A.M. & Sonnenschein, C. A novel 3D in vitro culture model to study stromal-epithelial interactions in the mammary gland. Tissue Eng. Part C Methods 14, 261–271 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Liang, C.C., Park, A.Y. & Guan, J.L. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat. Protoc. 2, 329–333 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to K. Polyak (Harvard Medical School) and M. Hu for providing MCF10DCIS parental cells and advice, C. Ambrosone, L. Hines, A. Thor and S. Edgerton for human tissue acquisition, M. Garcia and M. Skokan for FISH analysis, M. Lucia and R. Wilson for assistance with quantitative immunohistochemistry analysis, O. Maller, K. Bell, S. Jindal, K. Hedman, D. Powell, N. DeWaele and Y. Kwarteng for technical assistance, and S. Sillau for advanced statistical analyses. We thank K. Polyak, A. Thorburn, M. Moss and Nature Medicine reviewers for critical evaluation of the manuscript, and we gratefully acknowledge the subjects for their contribution to this research. This work was supported by Department of Defense Synergistic Idea Award BC060531, Komen Foundation grant KG090629, Mary Kay Ash Foundation grant 078-08, AMC cancer fund, and University of Colorado Cancer Center grants to P.S. and V.B., Department of Defense Award BC074970 to P.J.K., American Cancer Society New England Division Postdoctoral Fellowship Spin Odyssey PF-08-257-01-CSM to T.R.L., Department of Defense Postdoctoral grant BC087579 to A.M., and Department of Defense Predoctoral grant BC073482 to J.O.

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Author notes

  1. Traci R Lyons and Jenean O'Brien: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

    Traci R Lyons, Jenean O'Brien, Virginia F Borges, Aik-Choon Tan & Pepper Schedin

  2. Program in Cancer Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

    Jenean O'Brien & Pepper Schedin

  3. University of Colorado Cancer Center, Aurora, Colorado, USA

    Virginia F Borges, Aik-Choon Tan & Pepper Schedin

  4. Department of Cell and Regenerative Biology and UW Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, USA

    Matthew W Conklin & Patricia J Keely

  5. Laboratory of Cell and Molecular Biology, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison, Wisconsin, USA

    Matthew W Conklin, Patricia J Keely & Kevin W Eliceiri

  6. Department of Medical Oncology, Department of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Andriy Marusyk

  7. AMC Cancer Research Center, Denver, Colorado, USA

    Pepper Schedin

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  1. Traci R Lyons
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Contributions

T.R.L. developed the postpartum mouse model, and designed and performed the in vivo celecoxib, two-dimensional cell culture, protein expression, three-dimensional collagen, celecoxib, COX-2 knockdown and human DCIS studies, and data analyses. J.O. designed and performed the in vivo ibuprofen experiments, the collagen western blot quantification, the three-dimensional gelatin assay and data analyses. P.J.K. and M.W.C. performed quantitative SHG collagen imaging and collagen fiber orientation. K.W.E. provided critical guidance for the SHG imaging. A.M. generated GFP-expressing MCF10DCIS cells and provided MCF10DCIS cells with stable knockdown of COX-2. A.-C.T. performed the human outcome analyses. V.B. and T.R.L. were responsible for regulatory oversight of human tissue acquisition and V.B. and P.S. for human tissue acquisition. P.S. and V.B. were responsible for hypothesis development, conceptual design and all data analysis and interpretation. T.R.L., J.O. and P.S. wrote the manuscript.

Corresponding author

Correspondence to Pepper Schedin.

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The authors declare no competing financial interests.

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Lyons, T., O'Brien, J., Borges, V. et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 17, 1109–1115 (2011). https://doi.org/10.1038/nm.2416

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