RANK-ligand (RANKL) expression in young breast cancer patients and during pregnancy

Abstract

RANKL is important in mammary gland development during pregnancy and mediates the initiation and progression of progesterone-induced breast cancer. No clinical data are available on the effect of pregnancy on RANK/RANKL expression in young breast cancer patients. We used our previously published dataset of 65 pregnant and 130 matched young breast cancer patients with full clinical, pathological, and survival information. 85% of patients had available transcriptomic data as well. RANK/RANKL expression by immunohistochemistry using H-score on the primary tumor and adjacent normal tissue was performed. We examined the difference in expression of RANK/RANKL between pregnant and non-pregnant patients and their association with clinicopathological features and prognosis. We also evaluated genes and pathways associated with RANK/RANKL expression on primary tumors. RANKL but not RANK expression was more prevalent in the pregnant group, both on the tumor and adjacent normal tissue, independent of other clinicopathological factors (both P <0.001). 18.7% of pregnant and 5.3% of non-pregnant patients had tumors showing ≥10% of cells with 3+ RANKL expression. RANKL expression was significantly higher in progesterone receptor-positive, and luminal A-like tumors, with negative correlation with Ki-67 (all P <0.001). On the contrary, RANK expression was higher in triple negative tumors (P <0.001). Using false discovery rate <0.05, 151 and 1,207 genes were significantly correlated with tumor-expressed RANKL and RANK expression by immunohistochemistry, respectively. High RANKL expression within primary tumor was associated with pathways related to mammary gland development, bone resorption, T-cell proliferation and regulation of chemotaxis, while RANK expression was associated with immune response and proliferation pathways. At a median follow-up of 65 months, neither RANK nor RANKL expression within tumor was associated with disease free survival in pregnant or non-pregnant group. Pregnancy increases RANKL expression both in normal breast and primary tumors. These results could guide further development of RANKL-targeted therapy.