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Principal Investigator
Pepper J Schedin
Awardee Organization

Oregon Health & Science University
United States

Fiscal Year
2024
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

NSAIDs During Postpartum Involution for Breast Cancer Chemoprevention

While previously unrecognized, it is now documented that having delivered a child within 10 years is an independent predictor of early onset breast cancer and poor outcomes. These cancers, based largely on work from our labs, is now referred to as postpartum breast cancer (PPBC), and represents a significant clinical problem. Every year in the US alone, ~15,000 young women (accounting for ~50% of all young women’s breast cancer cases) are diagnosed during the high risk, postpartum period. Research in our lab has advanced the hypothesis that weaning-induced mammary gland involution is the driver of increased incidence and metastasis in PPBC patients. During the transitory window of weaning-induced involution, the normal involuting mammary gland is skewed towards a pro-tumor microenvironment, as it exhibits increased lymphangiogenesis, fibroblast activation, and extracellular matrix deposition; as well as enrichment for myeloid derived suppressor cells (MDSC), M2-skewed macrophages, and Th-17, Th-2 and Treg skewed T cells compared to nulliparous glands. These discoveries support our hypothesis that sub-clinical, non-life threatening disease progresses to overtly invasive cancer during weaning-induced involution. In multiple murine models, we confirm that the tissue microenvironment of the involuting gland increases mammary tumor incidence and progression. Further, we demonstrate that ibuprofen (IBU) treatment targeted to the involution window blocks >50% of these tumors from emerging, depending on model. Further, of those tumors that do emerge, progression to metastatic disease is suppressed. One mechanism by which IBU appears to inhibit PPBC is through anti-tumor immunity, as IBU increases the number of cytotoxic T cells, consistent with increased immune surveillance. Importantly, we find the ability of IBU to restore the adaptive arm of the immune system occurs in the absence of adverse host autoimmune reactions and does not impact the ability of dams to successfully nurse their young in subsequent pregnancies. These findings support clinical utility of IBU in the setting of a PPBC prevention trial. Our studies also identify opportunities to improve efficacy, and vitamin D (Vit D) is proposed based on its anti-tumor and anti-inflammatory activity, and its safety and particular relevance in postpartum women, who are at high risk for VitD deficiency. Here we propose to 1) investigate the efficacy of IBU treatment in combination with vitamin D, in rodent models of PPBC with improved human relevance, 2) identify the mechanism by which IBU +/- VitD mitigates the pro-tumorigenic microenvironment of the involuting gland with the goal of identifying additional involution-specific targets; and 3) translate our rodent studies defining the ‘immune composition of the “at risk” involuting mammary gland to women, by defining the immune milieu in the normal human breast across reproductive states. Only through understanding how the normal, involuting human breast confers increased BrCa risk, can we identify additional targets to improve the efficacy of our chemoprevention strategy and lay the foundation for PPBC prevention.

Publications

  • Bernhardt SM, Borges VF, Schedin P. Vitamin D as a Potential Preventive Agent For Young Women's Breast Cancer. Cancer prevention research (Philadelphia, Pa.). 2021 Sep;14(9):825-838. Epub 2021 Jul 9. PMID: 34244152
  • Goddard ET, Fischer J, Schedin P. A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer. Journal of visualized experiments : JoVE. 2016 Dec 26;(118). PMID: 28060292
  • Tung JC, Barnes JM, Desai SR, Sistrunk C, Conklin MW, Schedin P, Eliceiri KW, Keely PJ, Seewaldt VL, Weaver VM. Tumor mechanics and metabolic dysfunction. Free radical biology & medicine. 2015 Feb;79:269-80. Epub 2014 Dec 19. PMID: 25532934
  • Rosenberg SM, Sepucha K, Ruddy KJ, Tamimi RM, Gelber S, Meyer ME, Schapira L, Come SE, Borges VF, Golshan M, Winer EP, Partridge AH. Local Therapy Decision-Making and Contralateral Prophylactic Mastectomy in Young Women with Early-Stage Breast Cancer. Annals of surgical oncology. 2015 Nov;22(12):3809-15. Epub 2015 May 1. PMID: 25930247
  • Bartlett AQ, Pennock ND, Klug A, Schedin P. Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis. Cancers. 2021 Apr 3;13. (7). PMID: 33916683
  • Guo Q, Minnier J, Burchard J, Chiotti K, Spellman P, Schedin P. Physiologically activated mammary fibroblasts promote postpartum mammary cancer. JCI insight. 2017 Mar 23;2(6):e89206. PMID: 28352652
  • Jindal S, Narasimhan J, Borges VF, Schedin P. Characterization of weaning-induced breast involution in women: implications for young women's breast cancer. NPJ breast cancer. 2020 Oct 16;6:55. doi: 10.1038/s41523-020-00196-3. eCollection 2020. PMID: 33083533
  • Goddard ET, Hill RC, Nemkov T, D'Alessandro A, Hansen KC, Maller O, Mongoue-Tchokote S, Mori M, Partridge AH, Borges VF, Schedin P. The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis. Cancer discovery. 2017 Feb;7(2):177-187. Epub 2016 Dec 14. PMID: 27974414
  • Fornetti J, Flanders KC, Henson PM, Tan AC, Borges VF, Schedin P. Mammary epithelial cell phagocytosis downstream of TGF-β3 is characterized by adherens junction reorganization. Cell death and differentiation. 2016 Feb;23(2):185-96. Epub 2015 Jun 26. PMID: 26113040
  • Borges VF, Lyons TR, Germain D, Schedin P. Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments? Cancer research. 2020 May 1;80(9):1790-1798. Epub 2020 Feb 19. PMID: 32075799
  • Jindal S, Gao D, Bell P, Albrektsen G, Edgerton SM, Ambrosone CB, Thor AD, Borges VF, Schedin P. Postpartum breast involution reveals regression of secretory lobules mediated by tissue-remodeling. Breast cancer research : BCR. 2014 Mar 28;16(2):R31. PMID: 24678808
  • Bruno RD, Fleming JM, George AL, Boulanger CA, Schedin P, Smith GH. Mammary extracellular matrix directs differentiation of testicular and embryonic stem cells to form functional mammary glands in vivo. Scientific reports. 2017 Jan 10;7:40196. PMID: 28071703
  • Jeong J, Kim W, Hens J, Dann P, Schedin P, Friedman PA, Wysolmerski JJ. NHERF1 Is Required for Localization of PMCA2 and Suppression of Early Involution in the Female Lactating Mammary Gland. Endocrinology. 2019 Aug 1;160(8):1797-1810. PMID: 31087002
  • Fornetti J, Martinson HA, Betts CB, Lyons TR, Jindal S, Guo Q, Coussens LM, Borges VF, Schedin P. Mammary gland involution as an immunotherapeutic target for postpartum breast cancer. Journal of mammary gland biology and neoplasia. 2014 Jul;19(2):213-28. Epub 2014 Jun 22. PMID: 24952477
  • Maller O, Hansen KC, Lyons TR, Acerbi I, Weaver VM, Prekeris R, Tan AC, Schedin P. Collagen architecture in pregnancy-induced protection from breast cancer. Journal of cell science. 2013 Sep 15;126(Pt 18):4108-10. Epub 2013 Jul 10. PMID: 23843613
  • Betts CB, Pennock ND, Caruso BP, Ruffell B, Borges VF, Schedin P. Mucosal Immunity in the Female Murine Mammary Gland. Journal of immunology (Baltimore, Md. : 1950). 2018 Jul 15;201(2):734-746. Epub 2018 Jun 8. PMID: 29884705
  • Russell TD, Jindal S, Agunbiade S, Gao D, Troxell M, Borges VF, Schedin P. Myoepithelial cell differentiation markers in ductal carcinoma in situ progression. The American journal of pathology. 2015 Nov;185(11):3076-89. Epub 2015 Sep 4. PMID: 26343330
  • Fornetti J, Jindal S, Middleton KA, Borges VF, Schedin P. Physiological COX-2 expression in breast epithelium associates with COX-2 levels in ductal carcinoma in situ and invasive breast cancer in young women. The American journal of pathology. 2014 Apr;184(4):1219-1229. Epub 2014 Feb 8. PMID: 24518566
  • Bernhardt SM, Mitchell E, Stamnes S, Hoffmann RJ, Calhoun A, Klug A, Russell TD, Pennock ND, Walker JM, Schedin P. Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage. Cancers. 2023 Apr 12;15. (8). PMID: 37190184
  • Jindal S, Pennock ND, Sun D, Horton W, Ozaki MK, Narasimhan J, Bartlett AQ, Weinmann S, Goss PE, Borges VF, Xia Z, Schedin P. Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes. Nature communications. 2021 Nov 3;12(1):6341. PMID: 34732713
  • Shagisultanova E, Gao D, Callihan E, Parris HJ, Risendal B, Hines LM, Slattery ML, Baumgartner K, Schedin P, John EM, Borges VF. Overall survival is the lowest among young women with postpartum breast cancer. European journal of cancer (Oxford, England : 1990). 2022 Jun;168:119-127. Epub 2022 May 4. PMID: 35525161
  • Schedin P, Palmer JR. Can Breast Cancer Prevention Strategies Be Tailored to Biologic Subtype and Unique Reproductive Windows? Journal of the National Cancer Institute. 2022 Dec 8;114(12):1575-1576. PMID: 35723566
  • Goddard ET, Hill RC, Barrett A, Betts C, Guo Q, Maller O, Borges VF, Hansen KC, Schedin P. Quantitative extracellular matrix proteomics to study mammary and liver tissue microenvironments. The international journal of biochemistry & cell biology. 2016 Dec;81(Pt A):223-232. Epub 2016 Oct 24. PMID: 27771439
  • Palmer JR, Viscidi E, Troester MA, Hong CC, Schedin P, Bethea TN, Bandera EV, Borges V, McKinnon C, Haiman CA, Lunetta K, Kolonel LN, Rosenberg L, Olshan AF, Ambrosone CB. Parity, lactation, and breast cancer subtypes in African American women: results from the AMBER Consortium. Journal of the National Cancer Institute. 2014 Sep 15;106. (10). Print 2014 Oct. PMID: 25224496
  • Tamburini BAJ, Elder AM, Finlon JM, Winter AB, Wessells VM, Borges VF, Lyons TR. PD-1 Blockade During Post-partum Involution Reactivates the Anti-tumor Response and Reduces Lymphatic Vessel Density. Frontiers in immunology. 2019 Jun 11;10:1313. doi: 10.3389/fimmu.2019.01313. eCollection 2019. PMID: 31244852
  • Esbona K, Inman D, Saha S, Jeffery J, Schedin P, Wilke L, Keely P. COX-2 modulates mammary tumor progression in response to collagen density. Breast cancer research : BCR. 2016 Mar 22;18(1):35. PMID: 27000374
  • Chollet-Hinton L, Olshan AF, Nichols HB, Anders CK, Lund JL, Allott EH, Bethea TN, Hong CC, Cohen SM, Khoury T, Zirpoli GR, Borges VF, Rosenberg LA, Bandera EV, Ambrosone CB, Palmer JR, Troester MA. Biology and Etiology of Young-Onset Breast Cancers among Premenopausal African American Women: Results from the AMBER Consortium. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2017 Dec;26(12):1722-1729. Epub 2017 Sep 13. PMID: 28903991
  • Anczuków O, Airhart S, Chuang JH, Coussens LM, Kuchel GA, Korstanje R, Li S, Lucido AL, McAllister SS, Politi K, Polyak K, Ratliff T, Ren G, Trowbridge JJ, Ucar D, Palucka K. Challenges and opportunities for modeling aging and cancer. Cancer cell. 2023 Apr 10;41(4):641-645. Epub 2023 Mar 30. PMID: 37001528
  • Haricharan S, Dong J, Hein S, Reddy JP, Du Z, Toneff M, Holloway K, Hilsenbeck SG, Huang S, Atkinson R, Woodward W, Jindal S, Borges VF, Gutierrez C, Zhang H, Schedin PJ, Osborne CK, Tweardy DJ, Li Y. Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy. eLife. 2013 Dec 31;2:e00996. PMID: 24381245
  • Bethea TN, Rosenberg L, Hong CC, Troester MA, Lunetta KL, Bandera EV, Schedin P, Kolonel LN, Olshan AF, Ambrosone CB, Palmer JR. A case-control analysis of oral contraceptive use and breast cancer subtypes in the African American Breast Cancer Epidemiology and Risk Consortium. Breast cancer research : BCR. 2015 Feb 21;17(1):22. PMID: 25849024
  • Pennock ND, Jindal S, Horton W, Sun D, Narasimhan J, Carbone L, Fei SS, Searles R, Harrington CA, Burchard J, Weinmann S, Schedin P, Xia Z. RNA-seq from archival FFPE breast cancer samples: molecular pathway fidelity and novel discovery. BMC medical genomics. 2019 Dec 19;12(1):195. PMID: 31856832
  • Zhang Z, Ye S, Bernhardt SM, Nelson HD, Velie EM, Borges VF, Woodward ER, Evans DGR, Schedin PJ. Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants. JAMA network open. 2024 Apr 1;7(4):e247421. PMID: 38639936
  • Goddard ET, Bassale S, Schedin T, Jindal S, Johnston J, Cabral E, Latour E, Lyons TR, Mori M, Schedin PJ, Borges VF. Association Between Postpartum Breast Cancer Diagnosis and Metastasis and the Clinical Features Underlying Risk. JAMA network open. 2019 Jan 4;2(1):e186997. PMID: 30646210
  • Elder AM, Tamburini BAJ, Crump LS, Black SA, Wessells VM, Schedin PJ, Borges VF, Lyons TR. Semaphorin 7A Promotes Macrophage-Mediated Lymphatic Remodeling during Postpartum Mammary Gland Involution and in Breast Cancer. Cancer research. 2018 Nov 15;78(22):6473-6485. Epub 2018 Sep 25. PMID: 30254150
  • Collins LC, Gelber S, Marotti JD, White S, Ruddy K, Brachtel EF, Schapira L, Come SE, Borges VF, Schedin P, Warner E, Wensley T, Tamimi RM, Winer EP, Partridge AH. Molecular Phenotype of Breast Cancer According to Time Since Last Pregnancy in a Large Cohort of Young Women. The oncologist. 2015 Jul;20(7):713-8. Epub 2015 May 29. PMID: 26025931
  • Betts CB, Quackenbush A, Anderson W, Marshall NE, Schedin PJ. Mucosal Immunity and Liver Metabolism in the Complex Condition of Lactation Insufficiency. Journal of human lactation : official journal of International Lactation Consultant Association. 2020 Nov;36(4):582-590. Epub 2020 Aug 14. PMID: 32795211
  • Pennock ND, Martinson HA, Guo Q, Betts CB, Jindal S, Tsujikawa T, Coussens LM, Borges VF, Schedin P. Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer. Journal for immunotherapy of cancer. 2018 Oct 1;6(1):98. PMID: 30285905
  • Amant F, Lefrère H, Borges VF, Cardonick E, Lambertini M, Loibl S, Peccatori F, Partridge A, Schedin P. The definition of pregnancy-associated breast cancer is outdated and should no longer be used. The Lancet. Oncology. 2021 Jun;22(6):753-754. PMID: 34087122
  • Jordan KR, Hall JK, Schedin T, Borakove M, Xian JJ, Dzieciatkowska M, Lyons TR, Schedin P, Hansen KC, Borges VF. Extracellular vesicles from young women's breast cancer patients drive increased invasion of non-malignant cells via the Focal Adhesion Kinase pathway: a proteomic approach. Breast cancer research : BCR. 2020 Nov 23;22(1):128. PMID: 33225939
  • Guo Q, Betts C, Pennock N, Mitchell E, Schedin P. Mammary Gland Involution Provides a Unique Model to Study the TGF-β Cancer Paradox. Journal of clinical medicine. 2017 Jan 13;6. (1). PMID: 28098775
  • Guo Q, Sun D, Barrett AS, Jindal S, Pennock ND, Conklin MW, Xia Z, Mitchell E, Samatham R, Mirza N, Jacques S, Weinmann S, Borges VF, Hansen KC, Schedin PJ. Mammary collagen is under reproductive control with implications for breast cancer. Matrix biology : journal of the International Society for Matrix Biology. 2022 Jan;105:104-126. Epub 2021 Nov 25. PMID: 34839002
  • Ruszczyk M, Zirpoli G, Kumar S, Bandera EV, Bovbjerg DH, Jandorf L, Khoury T, Hwang H, Ciupak G, Pawlish K, Schedin P, Masso-Welch P, Ambrosone CB, Hong CC. Breast cancer risk factor associations differ for pure versus invasive carcinoma with an in situ component in case-control and case-case analyses. Cancer causes & control : CCC. 2016 Feb;27(2):183-98. Epub 2015 Nov 30. PMID: 26621543
  • Q Bartlett A, Vesco KK, Purnell JQ, Francisco M, Goddard E, Guan X, DeBarber A, Leo MC, Baetscher E, Rooney W, Naugler W, Guimaraes AR, Catalano P, Xia Z, Schedin P. Pregnancy and weaning regulate human maternal liver size and function. Proceedings of the National Academy of Sciences of the United States of America. 2021 Nov 30;118. (48). PMID: 34815335
  • Jindal S, Pennock ND, Klug A, Narasimhan J, Calhoun A, Roberts MR, Tamimi RM, Eliassen AH, Weinmann S, Borges VF, Schedin P. S-nitrosylated and non-nitrosylated COX2 have differential expression and distinct subcellular localization in normal and breast cancer tissue. NPJ breast cancer. 2020 Nov 24;6(1):62. PMID: 33298921
  • Ambrosone CB, Zirpoli G, Hong CC, Yao S, Troester MA, Bandera EV, Schedin P, Bethea TN, Borges V, Park SY, Chandra D, Rosenberg L, Kolonel LN, Olshan AF, Palmer JR. Important Role of Menarche in Development of Estrogen Receptor-Negative Breast Cancer in African American Women. Journal of the National Cancer Institute. 2015 Jun 17;107. (9). Print 2015 Sep. PMID: 26085483
  • Gray E, Mitchell E, Jindal S, Schedin P, Chang YH. A METHOD FOR QUANTIFICATION OF CALPONIN EXPRESSION IN MYOEPITHELIAL CELLS IN IMMUNOHISTOCHEMICAL IMAGES OF DUCTAL CARCINOMA IN SITU. Proceedings. IEEE International Symposium on Biomedical Imaging. 2018 Apr;2018:796-799. Epub 2018 May 24. PMID: 30364524
  • Lefrère H, Lenaerts L, Borges VF, Schedin P, Neven P, Amant F. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2021 Mar;31(3):412-422. PMID: 33649008
  • Bernhardt SM, Ozaki MK, Betts C, Bleyle LA, DeBarber AE, Fornetti J, Liberty AL, Wilde De E, Zhang Y, Xia Z, Schedin P. Altered liver metabolism post-wean abolishes efficacy of vitamin D for breast cancer prevention in a mouse model. bioRxiv : the preprint server for biology. 2024 Jun 2. PMID: 38854129
  • Lyons TR, Borges VF, Betts CB, Guo Q, Kapoor P, Martinson HA, Jindal S, Schedin P. Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer. The Journal of clinical investigation. 2014 Sep;124(9):3901-12. Epub 2014 Aug 18. PMID: 25133426
  • Martinson HA, Jindal S, Durand-Rougely C, Borges VF, Schedin P. Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression. International journal of cancer. 2015 Apr 15;136(8):1803-13. Epub 2014 Sep 15. PMID: 25187059