Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Moreover, the metastasis and mortality rates are strikingly higher in men than in women. Intriguingly, these gender differences in CRC are observed only in tumors that have a KRAS mutated (KRAS*) gene. The molecular basis for these gender differences is not known.

In our mouse model of KRAS* CRC, these gender differences are also observed, providing a genetic model with which to study the mechanisms underlying how KRAS* may regulate higher metastasis and poorer survival in males. Our preliminary data have uncovered that KRAS* activates STAT4 which directly up-regulates the level of a Y chromosome-linked d...

Read More

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Moreover, the metastasis and mortality rates are strikingly higher in men than in women. Intriguingly, these gender differences in CRC are observed only in tumors that have a KRAS mutated (KRAS*) gene. The molecular basis for these gender differences is not known.

In our mouse model of KRAS* CRC, these gender differences are also observed, providing a genetic model with which to study the mechanisms underlying how KRAS* may regulate higher metastasis and poorer survival in males. Our preliminary data have uncovered that KRAS* activates STAT4 which directly up-regulates the level of a Y chromosome-linked demethylase, named KDM5D. Further, KDM5D modifies chromatin (a collection of proteins that cloak the DNA to regulate the expression of specific genes). We observed that KDM5D modifies chromatin to repress cell-cell adhesion genes and MHC class I genes, which would result in increased cell motility and immune evasion, respectively. Elucidation of this molecular circuitry should provide novel druggable targets for men suffering from KRAS* CRC.

Read Less