Cyclooxygenase-2–dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer
Traci R. Lyons, … , Sonali Jindal, Pepper Schedin
Traci R. Lyons, … , Sonali Jindal, Pepper Schedin
Published August 18, 2014
Citation Information: J Clin Invest. 2014;124(9):3901-3912. https://doi.org/10.1172/JCI73777.
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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 5

COX-2–dependent lymphangiogenesis, lymphatic vessel invasion, and lung metastasis in a xenograft model of postpartum breast cancer.

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COX-2–dependent lymphangiogenesis, lymphatic vessel invasion, and lung m...
(A) shCOX-2 cells induce fewer branches in tube formation assays compared with shGFP MCF10DCIS (shGFP) vector controls. (B) Injection of shCOX-2 cells during involution results in decreased peritumoral LYVE1+ vessel density and (C) number of LYVE1+ vessels containing tumor cell nuclei compared with vector control cells. (D) Tumor cell COX-2 expression correlates with tumor-associated LYVE1+ vessel density (Pearson r = 0.6354). Involution group tumor cell (E) lysates and (F) conditioned media contain higher levels of PGE2 by ELISA. (G) LECs cultured in involution group tumor cell–conditioned media upregulate EP2 protein expression. (H) LECs cultured in nulliparous media and 10 μM PGE2 form larger structures, and LECs cultured in involution group tumor cell–conditioned media and EP2 antagonist (AH6809) at 5 μM and 10 μM form smaller structures (I) with fewer branches. In involution group animals, CXB diet (Inv+CXB) decreases (J) LYVE1+ vessel density in SCID mouse mammary glands during normal involution, (K) peritumoral LYVE1+ vessel density, (L) number of LYVE1+ vessels containing tumor cell nuclei, and (M) average number of lung micrometastasis per animal. CXB diet also decreased (N) peritumoral LYVE1+ vessel density and (O) lung metastasis in BALB/c mice with 66cl4 mammary tumors. All data points are depicted along with group average (black bar ± SEM). *P < 0.05, **P < 0.01, ***P < 0.001, t test.