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

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.

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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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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.

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Correspondence to Pepper Schedin.

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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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