Abstract B099: Postpartum mammary gland involution promotes COX-2 dependent tumor cell invasion of lymphatics

Abstract

Although tumor cell dissemination via the lymphatic vasculature is thought to be a common pathway of metastasis for solid human cancers, the mechanisms of lymphatic mediated metastasis remain poorly understood1. For breast cancer patients, lymph node involvement remains a very important indicator of patient prognosis and is utilized clinically for therapeutic choices2,3. A recent study has shown that the incidence of being diagnosed with stage IV breast cancer, i.e. breast cancer that has spread outside the breast, is increasing in young women4. Furthermore, young women's breast cancers diagnosed within 5 years postpartum are more likely to be metastatic5-7. Given that 35-45% of young women's breast cancers are likely to be diagnosed within 5 years of giving birth, we predict that postpartum cases may be driving the observed increase in breast cancers with distant involvement in young women. Here, we hypothesized that the postpartum period promotes lymphangiogenesis, which leads to breast tumor metastasis. To test this hypothesis we have generated xenograft and isograft mouse models of postpartum breast cancer that show increased metastasis in postpartum animals8,9. We utilized these rodent models and a cohort of young women's breast tissues to investigate lymphatic mediated metastasis in the postpartum period. In our rodent models, we show that 1) lymphangiogenesis is enhanced during normal postpartum involution, 2) tumor cells can utilize the lymphatic vasculature to escape the mammary gland during postpartum involution, 3) postpartum tumors display increased lymphatic vessel density and lymphatic vessel invasion in the tumor periphery, and 4) that postpartum tumor cells promote lymphangiogenesis and express high levels of pro-lymphangiogenic molecules VEGF-C and Sem7a ex vivo. Importantly, we show that both normal and tumor associated lymphangiogenesis in vivo are dependent upon COX-2 and that COX-2 inhibitors can block metastasis of postpartum tumors. In our young women's breast cancer cohort we also report increased mammary lymphangiogenesis tissues from women within one year of childbirth, increased lymphatic vessel density at the tumor periphery of postpartum breast cancers, as well as a positive correlation between lymphatic vessel density and lymphatic vessel invasion. Thus, we suggest that lymphatic mediated metastasis in young women may be decreased by COX-2 inhibitor or NSAID use. 1. Stacker, S.A., Baldwin, M.E. & Achen, M.G. The role of tumor lymphangiogenesis in metastatic spread. Faseb J 16, 922-934 (2002). 2. Alitalo, K. & Carmeliet, P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer cell 1, 219-227 (2002). 3. Pepper, M.S., Tille, J.C., Nisato, R. & Skobe, M. Lymphangiogenesis and tumor metastasis. Cell Tissue Res 314, 167-177 (2003). 4. Johnson, R.H., Chien, F.L. & Bleyer, A. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. Jama 309, 800-805 (2013). 5. 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). 6. Johansson, A.L., Andersson, T.M., Hsieh, C.C., Cnattingius, S. & Lambe, M. Increased Mortality in Women with Breast Cancer Detected during Pregnancy and Different Periods Postpartum. Cancer Epidemiol Biomarkers Prev 20, 1865-1872 (2011). 7. 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). 8. McDaniel, S.M., et al. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. The American journal of pathology 168, 608-620 (2006). 9. Lyons, T.R., et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 17, 1109-1115 (2011). Citation Format: Traci R. Lyons, Virginia F. Borges, Courtney B. Betts, Puja Kapoor, Holly A. Martinson, Sonali Jindal, Pepper Schedin. Postpartum mammary gland involution promotes COX-2 dependent tumor cell invasion of lymphatics. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B099.