The estrogen receptor α (ERα) is a major driver of breast cancer (BC), being expressed in 75% of diagnosed cases and promoting BC progression and metastasis. As a result, ERα is the major therapeutic target for ERα-positive BC, with agents such as tamoxifen and aromatase inhibitors being used to block ERα activity and interfere with its down-stream oncogenic singling. However, the major problem associated with these conventional therapies is the emergence of resistance, which occurs in up to 50% of patients. Resistant forms of BC are often associated with aggressive relapse, metastasis and high mortality rates of 80%. The crosstalk of ERα with other key (BC) drivers, namely the epidermal growth factor receptors (HER2, HER3, EGFR), progesterone receptor (PR), androgen receptor (AR) and prolactin receptor (PRL-R), further promotes disease progression and the development of drug resistance.
We assessed two novel anti-cancer agents, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which were developed in our lab. We found that these agents markedly reduced the expression of not only ERα but also the other major breast cancer drivers including: HER2, HER3, EGFR, PR, AR and PRL-R. Investigating the mechanisms behind this revealed that these agents promote the proteasomal degradation of ERα and that their effects are mediated via c-Jun, which is an inhibitor or ERα. Importantly, these agents also inhibited major genomic and non-genomic signaling pathways that promote ERα activity, as well as reducing the levels of key co-activators of ERα including SRC3, c-SRC, SP1 and c-MYC.
This study demonstrates for the first time the multi-faceted effect of these agents on multiple key drivers of BC progression and highlights their ability to overcome the major clinical problems of resistance and metastasis. This novel therapeutic approach may provide a safe and potent alternative for patients suffering advanced forms of BC