Table 1.
Protein | Mutation rate | Result of gene mutation | Response to retinoid treatment |
APC | 80%[57,65] | Loss of β-catenin degradation[58]; constitutive activation of the Wnt/β-catenin pathway[59]; decreased RDH levels inhibiting formation of ATRA[42] | Not determined |
β-Catenin | 5%[56] | Loss of β-catenin degradation[56]; constitutive activation of the Wnt/β-catenin pathway[56]; increased CYP26A1 levels resulting in increased degradation of ATRA | Increased degradation of β-catenin via RXR-mediated pathway[23,24] |
PI3K | 30%-50%[77,78] | Activation of Akt and loss of GSK3β function[80,82]; increased cancer metastasis[88], partially through NF-κB activation and increased expression of MMP-2 and -9[87,89,90]; positive cell cycle progression through cyclin D1[105]; loss of cell-cell adhesion by Snail accumulation to repress E-cadherin[106] | Decrease MMP-2 and MMP-9 activity[28]; increase TIMP-1 expression[28]; decrease the phosphorylation of GSK3β, decrease cellular proliferation, and increase the expression of pro-apoptotic proteins in human leiomyoma and myometrial cells[115]; CRBP-I inhibits PI3K/Akt activation in breast cancer cells[116]; inhibit PI3K activity to decrease CRC cell invasion in vitro and metastasis in vivo[25] |
PTEN | 20%-40%[80] | Loss of PI3K/Akt inhibition[80]; correlation with tumor aggressiveness and invasiveness[109-111] | Suppression of cellular proliferation and enhanced apoptosis by increasing PTEN expression in smooth muscle cells, neuroblastoma and glioblastoma cells, promyelocytes, leukemia cells, fibroblasts, and breast, endometrial, and hepatocellular carcinoma cells[119-128] |
COX-2 | 80%-90%[134-136] | Increased PGE2 signaling[133,137,138], ERK activation[140], PI3K/Akt signaling through increased EGFR[133,140,141], β-catenin stabilization[142,143], and MMP-2 and MMP-9 expression to promote cellular proliferation[144,145] | Decrease COX-2 expression[146], PGE2, β-catenin levels, and MMP-9[135,144]; inhibition of cell growth[151]; increased apoptosis and RARβ expression[152] |
PPARγ | 8%[161] | Loss of inhibitory action of gene transcription of pro-survival and growth amplification genes[155,162-165]; increased expression of COX-2[154] | Suppress COX-2 and MMP-7 expression and induction of cell cycle arrest and apoptosis[171]; induce expression of RARβ mRNA in breast cancer cells[175]; increase apoptosis in glioblastoma cells[176]; stimulate PTEN expression in leukemia cells and fibroblasts[121,128] |
p53 | 50%[177,178] | Loss of anti-growth and apoptotic activity; loss of p53/Siah-1-mediated β-catenin degradation[187] | Increase retinyl ester storage through transcription of retSDR1[54]; enhance p53-mediated cell cycle inhibition and apoptosis through activation of AP-2α and p21 in breast cancer cells[192], caspases in keratinocytes[188], Btg2 and CRABP-II in breast cancer cells[191]; STRA6 induction in ovarian cancer cells, fibroblasts, and CRC cells[193] |
APC: Adenomatous polyposis coli; RDH: Retinol dehydrogenase; ATRA: All-trans-retinoic acid; CYP26A1: Cytochrome P450 26A1; RXR: Retinoid X receptor; PI3K: Phosphatidylinositol-3-kinase; GSK3β: Glycogen synthase kinase 3β; NF-κB: Nuclear factor-kappa B; MMP: Matrix metalloproteinase; TIMP-1: Tissue inhibitor of matrix metalloproteinase 1; CRBP: Cellular retinol binding protein; CRC: Colorectal cancer; PTEN: Phosphatase and tensin homolog deleted on chromosome 10; COX2: Cyclooxygenase 2; PGE2: Prostaglandin E2; ERK: Extracellular signal-regulated kinase; EGFR: Epidermal growth factor receptor; RARβ: Retinoic acid receptor β; PPARγ: Peroxisome proliferator-activated receptor γ; AP-2α: Activator protein 2α; Btg2: Beta cell translocation gene 2; CRABP-II: Cellular retinoic acid binding protein II; STRA6: Stimulated by retinoic acid 6.