Abstract
Abstract 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.
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