Estrogen- and estrogen receptor (ER)-mediated cisplatin chemoresistance in cancer.

ABSTRACT

Cisplatin is a platinum-based chemotherapeutic drug used in the standard treatment of various solid cancers including testicular, bladder, head and neck, cervical and ovarian cancer. Although successful clinical responses are observed in patients following initial cisplatin treatment, resistance to cisplatin ultimately develops in most patients, leading to therapeutic failure. Multiple molecular mechanisms contributing to cisplatin resistance in cancer cells have been identified to date. In this review, we discuss the effect of estrogen, estrogen receptors (ERs) and estrogen-related receptors (ERRs) on cisplatin resistance in various cancer types. We highlight that estrogen treatment or increased expression of ERs or ERRs are generally associated with higher cisplatin resistance in cancer in vitro, mostly due to decreased caspase activity, increased anti-apoptotic protein levels such as BCL-2, higher drug efflux and higher levels of antioxidant enzymes. Targeted inhibition of ERs or estrogen production in combination with cisplatin treatment thus can be a useful strategy to overcome chemoresistance in certain cancer types. Estrogen levels and ER status can also be considered to identify cancer patients with a high potential of therapy response against cisplatin. A better mechanistic understanding of the involvement of estrogen, ERs and ERRs in the development of cisplatin resistance is needed to improve the management of cancer treatment.