Abstract B099: Postpartum mammary gland involution promotes COX-2 dependent tumor cell invasion of lymphatics
Authors: Lyons Traci R. , Borges Virginia F. , Betts Courtney B. , Kapoor Puja , Martinson Holly A. , Jindal Sonali , Schedin Pepper 
Published: May 2015

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.
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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.