Abstract B79: Postpartum mammary gland involution drives COX-2-dependent lymphangiogenesis and lymphatic vessel invasion in a model of postpartum breast cancer
Authors: Lyons Traci R. , Betts Courtney , Jindal Sonali , Kapoor Puja , Borges Virginia , Schedin Pepper 
Published: August 2014

Women diagnosed with breast cancer within five years postpartum have worse prognosis than age-matched nulliparous women, independent of tumor stage1,2. While lymph node involvement, lymphatic vessel presence at the tumor margin, and invasion of tumor cells into peritumor lymphatics are all poor prognostic factors for breast cancer patients1-3; it is unknown if lymphatic vessel invasion plays a role in the poor prognosis of postpartum breast cancer. To address this question, we utilized a cohort of young women's breast cancer cases balanced for patient age, tumor stage, and tumor biologic subtype. We observe increased lymph vessel density (LVD) and lymph vessel specific invasion (LSI) in the peritumor region of tumors from postpartum cases compared to nulliparous cases, consistent with a role for lymphatic vessel invasion in postpartum breast cancer metastasis. In addition, we observe increased LVD in normal mammary tissue from postpartum women suggesting that lymphangiogenesis is activated in the postpartum gland. We hypothesize that expansion of the lymphatic vasculature occurs during normal postpartum mammary gland regression, known as postpartum involution, and that tumor cells exposed to the involution microenvironment similarly upregulate lymphangiogenesis, providing increased opportunity for metastasis. To test this hypothesis, we measured LVD in normal rodent mammary tissues and observed a significant increase in LVD during postpartum mammary gland involution. We then utilized our mouse xenograft model of postpartum breast cancer to test whether postpartum tumors have increased LVD and LSI. In this model, postpartum tumors invade the surrounding mammary stroma and peripheral blood, and infiltrate the lung at increased frequency compared to nulliparous tumors4. Here, we also observe increased LVD and LSI in the peritumor region in the postpartum group. Furthermore, we utilized COX-2 inhibitors to show that COX-2 activity during involution is required for the increased LVD, LSI, and lung infiltration associated with postpartum tumors. COX-2 inhibitors also significantly reduced LVD in the normal gland during involution without interfering with morphological gland regression. Finally, tumor cells exposed to postpartum involution appear to be stably altered, as transplantation of postpartum tumor cells into nulliparous mice show elevated levels of tumor associated lymphatics. We conclude that tumor cells exploit the normal lymphangiogenesis programs of postpartum involution to persistently upregulate lymphangiogenesis, which may explain the increased metastasis observed in postpartum tumors. This work was funded by DOD, ACS, Komen, and Cancer League of Colorado.

References:

1. Schedin P. Pregnancy-associated breast cancer and metastasis. Nature reviews 2006;6:281-91.

2. Lyons TR, Schedin PJ, Borges VF. Pregnancy and breast cancer: when they collide. Journal of mammary gland biology and neoplasia 2009;14:87-98.

3. Jain RK, Padera TP. Prevention and treatment of lymphatic metastasis by antilymphangiogenic therapy. Journal of the National Cancer Institute 2002;94:785-7.

4. Lyons TR, O'Brien J, Borges VF, et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 2011;17:1109-15.

Citation Format: Traci R. Lyons, Courtney Betts, Sonali Jindal, Puja Kapoor, Virginia Borges, Pepper Schedin. Postpartum mammary gland involution drives COX-2-dependent lymphangiogenesis and lymphatic vessel invasion in a model of postpartum breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B79.