Role of Sex in the Therapeutic Targeting of p53 Circuitry

Francesca Mancini; Ludovica Giorgini; Emanuela Teveroni; Alfredo Pontecorvi; Fabiola Moretti

doi:10.3389/fonc.2021.698946

Role of Sex in the Therapeutic Targeting of p53 Circuitry

Front Oncol. 2021 Jul 8:11:698946. doi: 10.3389/fonc.2021.698946. eCollection 2021.

Authors

Francesca Mancini¹, Ludovica Giorgini^{2

3}, Emanuela Teveroni¹, Alfredo Pontecorvi³, Fabiola Moretti²

Affiliations

¹ Research Unit on Human Reproduction, International Scientific Institute Paul VI, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy.
² Institute of Biochemistry and Cell Biology, National Research Council of Italy, Monterotondo, Italy.
³ Catholic University of the Sacred Heart of Rome, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy.

Abstract

Sex profoundly affects cancer incidence and susceptibility to therapy, with sex hormones highly contributing to this disparity. Various studies and omics data suggest a relationship between sex and the oncosuppressor p53 circuitry, including its regulators MDM2 and MDM4. Association of this network with genetic variation underlies sex-related altered cancer risk, age of onset, and cancer sensitivity to therapy. Moreover, sex-related factors, mainly estrogenic hormones, can affect the levels and/or function of the p53 network both in hormone-dependent and independent cancer. Despite this evidence, preclinical and clinical studies aimed to evaluate p53 targeted therapy rarely consider sex and related factors. This review summarizes the studies reporting the relationship between sex and the p53 circuitry, including its associated regulators, MDM2 and MDM4, with particular emphasis on estrogenic hormones. Moreover, we reviewed the evaluation of sex/hormone in preclinical studies and clinical trials employing p53-target therapies, and discuss how patients' sex and hormonal status could impact these therapeutic approaches.

Keywords: MDM2; MDM4; cancer therapy; estrogen; p53; sex.

Publication types

Review