Abstract P1-07-11: Promotion of lymphangiogenesis by postpartum breast tumor cells

Abstract

Abstract Multiple studies report poor survival rates in postpartum women with breast cancer[1, 2]. A recent study from our group has specifically shown that incidence of recurrence and death from breast cancer is increased approximately 3-fold in postpartum patients compared to nulliparous patients[3]. We define postpartum breast cancers as those diagnosed within 5 years of birth and as a highly metastatic subset of young women’s breast cancer[4]. We have recently shown increased incidence of lymph node involvement in patients diagnosed less than 2 years postpartum and have utilized tissues from our clinical cohort to show increased lymphatic vessel density in stage II postpartum patient samples compared to nulliparous. Using xenograft and isograft murine models we have modeled postpartum breast cancer to show that postpartum tumors are larger[5], exhibit increased lymphatic vessel density, and more frequently spread to mouse lymph node and lung tissues[5] compared to tumors in nulliparous mice. In order to determine whether postpartum tumor cells specifically promote lymphangiogenesis, we utilized postpartum tumor cells ex vivo to show that lymphatic structure formation is promoted via increased postpartum tumor cell secretion of PGE2, which acts on the EP2 receptor on lymphatic endothelial cells. We have also performed expression analyses on postpartum tumor cells isolated from our xenograft model to reveal increased expression of COX-2, VEGF-C, and Semaphorin 7a; all three of these molecules have reported, and possibly interrelated, roles in promotion of lymphangiogenesis[6, 7]. Importantly, both in vivo inhibition and knockdown of COX-2 decrease postpartum tumor associated lymphangiogenesis in pre-clinical models. These results, along with our results indicating that COX-2 inhibition during the postpartum period decreases metastasis in our pre-clinical models, have led us to propose that COX-2 dependent promotion of lymphangiogenesis may facilitate, in part, metastasis of postpartum tumors. 1. Stensheim, H., et al., Cause-specific survival for women diagnosed with cancer during pregnancy or lactation: a registry-based cohort study. J Clin Oncol, 2009. 27(1): p. 45-51. 2. Johansson, A.L., et al., Increased Mortality in Women with Breast Cancer Detected during Pregnancy and Different Periods Postpartum. Cancer Epidemiol Biomarkers Prev, 2011. 20(9): p. 1865-72. 3. Callihan, E.B., 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): p. 549-59. 4. Lyons, T.R., P.J. Schedin, and V.F. Borges, Pregnancy and breast cancer: when they collide. J Mammary Gland Biol Neoplasia, 2009. 14(2): p. 87-98. 5. Lyons, T.R., et al., Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med, 2011. 17(9): p. 1109-15. 6. Timoshenko, A.V., et al., COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br J Cancer, 2006. 94(8): p. 1154-63. 7. Bender, R.J. and F. Mac Gabhann, Expression of VEGF and semaphorin genes define subgroups of triple negative breast cancer. PLoS One, 2013. 8(5): p. e61788. Citation Format: Traci R Lyons, Sarah A Black, Bernard W Futscher, Virginia F Borges, Pepper J Schedin. Promotion of lymphangiogenesis by postpartum breast tumor cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-11.