Evolution of MUC1 During Retrotransposon Expansion as a Potential Adaptation Exploited in Human Cancer

The MUCIN 1 (MUC1) gene evolved in eutherian mammals in association with the marked expansion of endogenous retroviruses (ERVs). MUC1 encodes the MUC1-C/M1C protein that protects barrier epithelia from exogenous viruses. Activation of M1C in response to loss of homeostasis induces STAT1 and the type I interferon (IFN-I) pathway. Studies in cancer cells have found that M1C regulates human ERV (HERV) expression by a STAT1-mediated mechanism. These discoveries have uncovered new insights into M1C-induced regulation of HERVs and other retrotransposons, such as LINE-1 (L1) and Alu. M1C signaling integrates retrotransposon transcription with induction of the counteracting apolipoprotein B mRNA-editing catalytic 3 (APOBEC3) genes that, like MUC1, first appeared in placental mammals. Activation of retrotransposons induces viral mimicry characterized as an IFN-I response that promotes innate anti-tumor immunity. Conversely, M1C protects cancer cells by sustained induction of the IFN-I pathway and immune evasion. This review posits that M1C-dependent regulation of retrotransposon and APOBEC3 expression represents an adaptive response exploited by cancer cells that promotes malignant progression.