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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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 1

Postpartum breast cancers exhibit increased lymph node metastasis and lymphatic vessel density.

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Postpartum breast cancers exhibit increased lymph node metastasis and ly...
(A) Percentage of lymph node (LN) positivity is increased in women diagnosed with breast cancer within 2 years postpartum (<2 PP) (n = 38) compared with women who have never been pregnant (NBP) (n = 190). (B) Similar percentages of tumor subtypes are observed in postpartum and nulliparous groups: luminal A (LumA), luminal B (LumB), unknown luminal [Lum(unk)] (ER status was positive but PR unknown), Her2, or triple-negative (TN) subtype. (C) Peritumor D2-40+ vessel density is increased in breast cancers diagnosed within 3 years of last childbirth (<3) in comparison to that in women who have never been pregnant (exact P = 0.0186). (D) Increased peritumor D2-40+ vessel density observed in the <3 group is not significantly increased by any known tumor biologic subtype. Color coding shows the reproductive-based tumor categories when separated by subtype. (E) D2-40+ vessel density correlates with number of D2-40+ vessels containing tumor cell nuclei (Pearson r = 0.5811). (F) Representative image of tumor cell lymphatic invasion in a D2-40+/Ki67-stained breast cancer specimen. Tissue sections were stained for Ki67 (right) then for D2-40 (left). (G) D2-40+ lymphatic vessel density is increased in normal adjacent breast tissue from women biopsied less than or equal to 1-year postpartum (≤1), compared with women biopsied 1–3 (>1≤3), 3–6 (>3≤6), 6–10 (>6≤10), 10–15 (>10≤15), and greater than 15 (>15) years postpartum and women who have never been pregnant. (H) Representative image depicting D2-40+ vessels containing cellular debris (arrow) or cells (arrowhead) in breast tissue obtained during 2 weeks after lactation. All data points are depicted along with group average (black bar ± SEM). Scale bar: 10 μm. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, t test.