Kidney disease accelerates breast cancer growth

Various observational studies have reported that chronic kidney disease (CKD) is associated with cancer development. However, the mechanisms underpinning these associations are still to be addressed. Therefore, the present study aimed to investigate whether CKD can stimulate tumor growth using two experimental models, and to identify pathophysiological pathways that may be involved.

An orthotopic model of breast cancer was established by injecting 2.5×105 E0771 breast cancer cells into the mammary fat pad of 10-week-old female C57BL/6J mice. Subsequently, unilateral ureteral obstruction (UUO) was induced in the left kidney 7 days after cancer cell implantation to induce CKD. In a separate study, UUO surgery was performed on the left kidney of 10 to 14-week-old female genetic MMTV-PvVT mice, which are prone to developing breast cancer. Sham surgeries were performed in both models without ureteral ligation.

In both models, the percentage of fibrosis in the kidney tissue (C57BL/6JE0771 (C): Fc = 6.88| p < 0.0001; MMTV-PyMT (M): Fc = 12.7 | p < 0.0001) and the plasma levels of creatinine (C: Fc = 1.17 | p = 0.0025; M: Fc = 1.36 | p < 0.0001) were significantly higher in the UUO mice compared to the sham mice. This effect was accompanied by a several fold upregulation in the mRNA expression of fibrotic genes, including α-SMA, TGFβ, Col1α1, Col3α1, Col4α1, Fn1, and CTGF, as well as inflammatory genes including IL-1β, MCP-1 and TNF-α (p <0.05). In Both xenograft and genetic model of breast cancer tumor volume (C: Fc = 1.95 | p = 0.0175; M: Fc = 3.37 | p = 0.0214) and tumor weight (C: Fc = 1.68 | p = 0.026; M: Fc = 2.12 | p = 0.0009) were significantly increased in the UUO mice compared to the sham mice. UUO induced proteomic changes in kidney, plasma and tumor tissues, and several proteomic changes were correlated with tumor size (p <0.05). Subsequent pathway analyses showed that inflammatory and fibrosis pathways were upregulated in the UUO kidneys, and that complement activation was upregulated in the UUO kidneys and plasma (p <0.05). As for tumor tissues, downregulation of apoptotic and aerobic respiration pathways was observed in UUO groups.

We demonstrate that CKD leads to increased breast tumor growth in two different mice models, suggesting a causal link between CKD and cancer. Pathway analyses indicate that inflammation and complement activation, extracellular matrix organization and angiogenesis are potential mechanisms explaining this relationship.