Abstract SY38-02: Postpartum tissue remodeling drives breast cancer metastasis

摘要: Women diagnosed with breast cancer within 10 years of a completed pregnancy are at ~2-3 fold increased risk for developing metastatic disease (1,2). This metastasis is independent tumor stage and biologic subtype, implicating tumor-extrinsic biology unique to the postpartum woman (3,4). Further, 30-50% all young women have had last (4), making diagnosis an poor prognostic indicator significant number patients. One event that may drive progression in rodents (5-8) (9) weaning-induced mammary gland involution, physiologic tissue remodeling process shares numerous attributes protumorigenic wound healing. We developed rodent models designed mimic this highly subset women9s find involution supports growth, dissemination, escape secondary organs COX-2 dependent manner (6,10,11). Here we extend these studies by investigating from mucosal organ perspective, as identifying links its associated immune suppression provide insight into prognosis cancers. While not classically considered organ, bacteria routinely interface luminal epithelium during lactation, necessitating barrier function. Similar defenses anticipated milk stasis increases mastitis. key immunologic hallmark presence distinct CD4+ helper T-cell subset, Th17 cells. cells stimulate epithelial cell junction integrity secretion mucins defensins, mechanisms barricade against bacterial activation antitumor Th1 Within baseline program T cells, which elevated lactating involuting glands. Mucosal features further expanded include tolerogenic dendritic phenotypes, barrier-supportive antimicrobials, alternatively activated Th2 immunosuppressive Treg CD4+T mammary-derived antigen-dependent activation, data consistent tolerance. also antigen-independent accumulation memory Th17- inflammation. Overall, elucidate strong programs immune-suppressive gland. Tumor microenvironment avoid detection readily gland, mechanism contribute observed Importantly, successfully metastasize, must only primary tumor, but seed grow site. Thus, additional potential confer through involution-specific changes sites. report evidence such advantage liver hosts. Using both intracardiac portal vein models, post-weaning seeding murine compared livers nulliparous control mice (12). Relevance suggested obtained cohort patients, where tropism specifically In rodents, driving previously unrecognized process. Post weaning, 50% reduction volume, hepatocyte death, deposition fibrillar collagen tenascin-c, matrix metalloproteinase activity, influxes populations phenotypes (12,13). These tissue-level establishment prometastatic niche involution. Combined, our supportive being hormone-responsive, immune-suppressed suggest hormone-responsive functionally coordinated cycle pregnancy, weaning. identify stromal mediator window. findings shed light on how normal reproductive physiology, interfaced remodeling, alters site-specific metastasis. framework necessary investigate target prevention women.References: 1. Johansson AL et al. Increased mortality detected different periods postpartum. Cancer Epidemiol Biomarkers Prev 2011;20(9):1865-72. 2. Lambe M Transient increase after giving birth. N Engl J Med 1994;331(1):5-9. 3. Schedin P. Pregnancy-associated Nat Rev 2006;6(4):281-91. 4. Callihan EB Postpartum demonstrates high merits definition pregnancy-associated cancer. Breast Res Treat 2013;138(2):549-59. 5. Guo Q Physiologically fibroblasts promote JCI Insight 2017;2(6):e89206. 6. Martinson HA Wound healing-like facilitates progression. Int 2015;136(8):1803-13. 7. McDaniel SM Remodeling lactation promotes Am Pathol 2006;168(2):608-20. 8. O9Brien Alternatively macrophages characterize across species. 2010;176(3):1241-55. 9. Jindal S reveals regression secretory lobules mediated tissue-remodeling. 2014;16(2):R31. 10. Lyons TR Cyclooxygenase-2-dependent lymphangiogenesis nodal Clin Invest 2014;124(9):3901-12. 11. drives ductal carcinoma situ COX-2. 2011;17(9):1109-15. 12. Goddard ET The undergoes Discov 2017;7(2):177-87. 13. Quantitative extracellular proteomics study microenvironments. Biochem Cell Biol 2016;81(Pt A):223-32. Citation Format: Courtney Betts, Nathan Pennock, Erica Goddard, Qiuchen Guo, Sonali Jindal, Virginia F. Borges, Pepper Jo Schedin, Alex Quackenbush. [abstract]. In: Proceedings American Association Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; 2018;78(13 Suppl):Abstract nr SY38-02.