We conclude that BHLHE40 overexpression does not always indicate increased activity, such as in breast cancer, where it is expressed in the cytoplasm, suppressing cell growth by stabilizing cyclin E. In the nucleus, BHLHE40 either suppressed tumors by inhibiting the expression of STAT1 or promoted tumor progression by activating the PI3K/Akt/mTOR pathway or by repressing AMPK. Here, BHLHE40 is linked to breast cancer.