Cyclooxygenase-2–dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer
Traci R. Lyons, Virginia F. Borges, Courtney B. Betts, Qiuchen Guo, Puja Kapoor, Holly A. Martinson, Sonali Jindal, Pepper Schedin
Traci R. Lyons, Virginia F. Borges, Courtney B. Betts, Qiuchen Guo, Puja Kapoor, Holly A. Martinson, Sonali Jindal, Pepper Schedin
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Research Article

Cyclooxygenase-2–dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer

Abstract

Breast involution following pregnancy has been implicated in the high rates of metastasis observed in postpartum breast cancers; however, it is not clear how this remodeling process promotes metastasis. Here, we demonstrate that human postpartum breast cancers have increased peritumor lymphatic vessel density that correlates with increased frequency of lymph node metastases. Moreover, lymphatic vessel density was increased in normal postpartum breast tissue compared with tissue from nulliparous women. In rodents, mammary lymphangiogenesis was upregulated during weaning-induced mammary gland involution. Furthermore, breast cancer cells exposed to the involuting mammary microenvironment acquired prolymphangiogenic properties that contributed to peritumor lymphatic expansion, tumor size, invasion, and distant metastases. Finally, in rodent models of postpartum breast cancer, cyclooxygenase-2 (COX-2) inhibition during the involution window decreased normal mammary gland lymphangiogenesis, mammary tumor-associated lymphangiogenesis, tumor cell invasion into lymphatics, and metastasis. Our data indicate that physiologic COX-2–dependent lymphangiogenesis occurs in the postpartum mammary gland and suggest that tumors within this mammary microenvironment acquire enhanced prolymphangiogenic activity. Further, our results suggest that the prolymphangiogenic microenvironment of the postpartum mammary gland has potential as a target to inhibit metastasis and suggest that further study of the therapeutic efficacy of COX-2 inhibitors in postpartum breast cancer is warranted.

Authors

Traci R. Lyons, Virginia F. Borges, Courtney B. Betts, Qiuchen Guo, Puja Kapoor, Holly A. Martinson, Sonali Jindal, Pepper Schedin

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Figure 4

Postpartum tumor cells promote lymphangiogenesis and express increased VEGF-C.

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Postpartum tumor cells promote lymphangiogenesis and express increased V...
Conditioned media from tumor cell populations collected from postpartum mice injected with MCF10DCIS tumor cells at day 1 of involution (n = 4) increased (A) LEC migration and LEC organoid complexity, as measured by (B) surface area, (C) organoid branching, and (D and E) VE-cadherin protein expression in tube formation assays, in comparison to nulliparous tumor cell (N, n = 3) conditioned media. Data from 2 to 3 replicate experiments per cell line are shown. Representative IF images of LEC organoids showing increased junctional VE-cadherin with conditioned media from involution group tumor cells compared with nulliparous media. (F) CC3 protein expression is decreased in LEC organoids cultured in conditioned media from involution group tumor cells. Involution group tumor cell populations also increase (G) peritumor LYVE1+ vessel density and (H) number of LYVE1+ vessels containing tumor cell nuclei when injected into nulliparous hosts (Inv→N) compared with nulliparous group tumor cells (N→N). All data points are depicted along with group average (black bar ± SEM). Scale bar: 5 μm. *P < 0.05, **P < 0.01, t test.