A dual role for COP1 in breast cancer

Estrogens drive cell proliferation and survival of breast cancer through binding to ERα. As a result, tamoxifen, an anti-estrogenic drug, is largely used to treat ERα+ breast cancers. However, a subclass of invasive breast cancers, the so-called Triple-negative breast cancer (TNBC) subtype, lacks ERα and is more challenging to cure. Exploring how ERα expression is regulated in breast cancer is critical to better understand why ERα is lost in more aggressive breast cancers. The team showed that COP1, an E3 ligase involved in the degradation of various proteins such as the transcription factor c-Jun, also promotes the degradation of HPIP, a microtubule-associated protein involved in the activation of the pro-survival kinase AKT. As a result, COP1 negatively regulates estrogens-dependent AKT activation in breast cancer cells. However, COP1 also induces ERα expression and ERα-dependent gene transcription, at least through c-Jun degradation. These findings are clinically relevant as COP1 and ERα levels are positively correlated in human cases of breast cancer. COP1 also supports the metabolic reprogramming induced by estrogens, including glycolysis. Collectively, these results define COP1 as an oncogenic protein in ERα+ breast cancers. On the other hand, COP1 suppresses the epithelial-mesenchymal transition (EMT), a cellular process which increases the invasiveness of breast cancer cells. COP1 deficiency also contributes to tamoxifen resistance, at least through protective autophagy, a process through which breast cancer cells escape from death induced by chemotherapeutic drugs. Therefore, COP1 acts as an oncogenic E3 ligase by promoting ERα signaling but also acts as a tumor suppressor candidate by preventing EMT, which reflects a dual role of COP1 in breast cancer.

Reference : Tang et al. (2021) Oncogene https://doi.org/10.1038/s41388-021-02038-3

Source : Alain Chariot

Photo : Alain Chariot