Effect of Wnt5a on drug resistance in estrogen receptor-positive breast cancer

Abstract

Background Previously, we reported that Wnt5a-positive breast cancer can be classified as estrogen receptor (ER)-positive breast cancer; its prognosis is worse than that of Wnt5a-negative breast cancer. This study aimed to investigate the mechanisms underlying the poor prognosis in Wnt5a-positive breast cancer patients. Methods In total, 151 consecutive ER-positive breast cancer patients who underwent resection between January 2011 and February 2014 were enrolled. DNA microarray and pathway analyses were conducted using MCF-7 cells stably expressing Wnt5a [MCF-7/Wnt5a (+)]. Based on the outcomes, cell viability/drug sensitivity assays, and mutation analysis were performed using cell cultures and breast cancer tissues. The relationship between Wnt5a and the PI3K–AKT–mTOR signaling pathway was also examined. Results The relapse-free survival rate in patients with Wnt5a-positive breast cancer was significantly lower than that in patients with Wnt5a-negative breast cancer (P = 0.047). DNA microarray data suggest that only the cytochrome P450 (CYP) pathway was significantly upregulated in MCF-7/Wnt5a (+) cells (P = 0.0440). Additionally, MCF-7/Wnt5a (+) cells displayed reduced sensitivity to the metabolic substrates of CYP, tamoxifen (P < 0.001), paclitaxel (P < 0.001), and cyclophosphamide (P < 0.001). Of note, PIK3CA mutations were not associated with the expression of Wnt5a in breast cancer tissue and culture cells. Conclusions In ER-positive breast cancer, Wnt5a upregulates the CYP metabolic pathway and suppresses tamoxifen, paclitaxel, and cyclophosphamide resistance, all of the three, standard treatment methods for ER-positive breast cancer. Wnt5a is thus potentially involved in the poor prognosis of ER-positive breast cancer independently of the PI3K–AKT–mTOR signaling pathway.

Transcriptomics and metabonomics study on the effect of exercise combined with curcumin supplementation on breast cancer in mice

“…3 C. Wnt signalling and insulin sensitivity are known to be significantly altered due to exercise intervention in breast cancer survivors (BCS) [ 52 ]. WNT5A has been identified as an essential regulator and therapeutic target in breast cancer [ [53] , [54] , [55] , [56] ]. Crosstalk between multiple inflammatory cytokines, including IL6 and IL-17, has been found to occur in the breast tumour microenvironment [ 57 ].…”

Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity

“…The progesterone-PGRMC1 signaling pathway and the sumoylation status of PGRMC1 also seem to modulate apoptosis by regulating the activity of the transcription factor Tcf/Lef [ 140 ], which is activated through the Wnt/β-catenin pathway. This mechanism has been shown to modulate CYP expression [ 170 , 171 , 172 , 173 ], interplaying with aryl hydrocarbon receptor (AhR) and constitutive androstane receptor (CAR) activation, both important trans-factors in the regulation of CYP expression [ 174 , 175 ].…”