17β-Estradiol strongly inhibits azoxymethane/dextran sulfate sodium-induced colorectal cancer development in Nrf2 knockout male mice

Nuclear Factor Erythroid 2-related Factor 2 Knockout Suppresses the Development of Aggressive Colorectal Cancer Formation Induced by Azoxymethane/Dextran Sulfate Sodium-Treatment in Female Mice

“…WT (Nrf2 +/+ ) and homozygous Nrf2 KO (Nrf2 −/− ) mice were obtained by crossing the Nrf2 heterozygous (Nrf2 +/− ) mice (Fig. 1A) as described previously [24]. The mice were housed in cages at 23°C with a 12/12-hour light/dark cycle under specific pathogen-free conditions.…”

“…For the induction of colitis-associated CRC, 2.5% (w/v) DSS (Cat no 160110; MP Biomedicals, Solon, OH, USA) was supplied in the drinking water for 7 days, one week following the injection of AOM (10 mg/kg) (Cat no A5486; Sigma-Aldrich, St. Louis, MO, USA) counted as day 0 [24,26]. WT and Nrf2 KO female mice were randomized into the following groups.…”

“…Clinical symptoms were evaluated using the disease activity index (DAI), which includes loss of body weight, stool characterization, and hematochezia [27,28]. The DAI was scored by two researchers in a blinded manner as described elsewhere [24].…”

“…We previously reported that 17β-estradiol (10 mg/ kg) reduced the expression of Nrf2 upregulated in AOM/ DSS-treated male ICR mice and suppressed the occurrence of colitis-related CRC to a level similar to that of females [23]. However, the inhibitory effect of 17β-estradiol (10 mg/kg) on expression of Nrf2 in C57BL/6 background male mice (wildtype, WT) was not sufficient to inhibit tumorigenesis in the distal colon [24]. In contrast, in the absence of Nrf2 (Nrf2 KO), 17β-estradiol (10 mg/kg) strongly inhibited tumorigenesis in the distal colon through an Nrf2-independent estrogen receptor beta (ERβ)-related signaling pathway [24].…”

“…However, the inhibitory effect of 17β-estradiol (10 mg/kg) on expression of Nrf2 in C57BL/6 background male mice (wildtype, WT) was not sufficient to inhibit tumorigenesis in the distal colon [24]. In contrast, in the absence of Nrf2 (Nrf2 KO), 17β-estradiol (10 mg/kg) strongly inhibited tumorigenesis in the distal colon through an Nrf2-independent estrogen receptor beta (ERβ)-related signaling pathway [24]. From these observations, we hypothesized that the contribution of Nrf2 to colitis-associated colon tumorigenesis could vary by sex.…”