The effects of estrogen on targeted cancer therapy drugs

Abstract

Improving the efficacy of anticancer drugs is especially challenging. Estrogen is a sex hormone that not only promotes the development of female secondary sexual characteristics, but also supports many important physiological functions. Interestingly, estrogen has shown to be vital for the activity of some anticancer drugs, such as adriamycin, cisplatin, olaparib, trastuzumab, bevacizumab, tamoxifen, cyclophosphamide, methotrexate, and paclitaxel. Although there are many reasons for the differences in therapeutic effects among cancer patients, estrogen status is undoubtedly a very important factor. In view of the importance of the crosstalk between estrogen signaling and drug therapy for cancer, this review summarizes the effects of estrogen on the targets, metabolism and resistance of anticancer drugs and describes the related pathways and underlying mechanisms. Here, an analysis of the close relationship between estrogen and cancer drug therapy was conducted to clarify the effects of estrogen on the therapeutic efficacy of anticancer drugs to facilitate the future development of specific drug treatment strategies to achieve optimal outcomes.

Introduction

Cancer is a major public health burden worldwide [1]. Many therapeutics have been developed to inhibit abnormal cell growth and metastasis, as well as to relieve pain and prolong the survival of cancer patients.

Estrogen is a female sex hormone secreted by the ovaries and placenta that promotes the development of female secondary sexual characteristics and participates in endocrine regulation [2]. Moreover, estrogen is also synthetized in some peripheral tissues, for instance, adipose tissue is the main site of estrogen production for post-menopausal women [2]. As specific mediators of estrogen activities, estrogen receptors (ESRs) are widely distributed in both reproductive and non-reproductive human tissues, including the uterus, vagina, breast, pelvis, skin, bladder, urethra, bone, and brain, and support many important physiological functions [3].

By binding to ESRs, estrogen affects the progression of some hormone-dependent cancers, such as breast, endometrial, prostate, ovarian, and thyroid cancers [4]. Studies conducted in the early 1980 s concluded that ESR status is a reliable marker of the efficacy of anticancer drugs for treatment of advanced breast cancer (BC) [5]. More recent studies have found that the regulation of estrogen is vital to the efficacy of cancer drug therapy, although the results have been inconsistent [6], [7], [8], [9].

In the classical estrogen signaling pathway, binding of estradiol (E2) to ESR1 and ESR2, which act as ligand-activated transcription factors, in the cytoplasm triggers a conformational change and induces receptor dimerization. This complex is then translocated to the nucleus and binds to the chromatin at estrogen response element sequences—enhancer regions within or close to promoters and/or 3’-untranlated regions of target genes—to activate or inhibit the expression of downstream genes, including those that influence pharmacodynamics, pharmacokinetics, and drug resistance [10]. The DNA binding domains of ESR1 and ESR2 are highly homologous, allowing them to share the same general structure, utilize the same estrogen response elements, and interact with the same coregulatory factors [11]. However, there are also differences in DNA binding domains between ESR1 and ESR2, which makes ESR1 and ESR2 exhibit different tissue distribution and biological effects. ESR1 gene expression profile showed up-regulated expression of cell growth-related genes [12]. ESR2 regulatory genes have a variety of functions, including signal transduction pathways, genes that regulate cell cycle progression and apoptosis [13]. In addition, the expression of one receptor affects the action of the other. By analyzing the gene regulation of ESR1- and ESR2 -mediated T47D cell lines, it was found that ESR2 had different effects on the expression of ESR1 regulatory genes, and either enhanced or inhibited the effect of ESR1 [14]. The ESR1:ESR2 ratio has been determined and used to study the overall estrogen reactivity of some cells expressing both the two receptors [11]. As a "non-classical" ESR signaling pathway, G protein-coupled estrogen receptor 1 (GPER1) mediates the rapid response to estrogen in the cytoplasm [15], [16].

The aims of this review article are to summarize the effects of estrogen on the efficacy of anticancer drugs and to clarify the associated pathways and underlying mechanisms. The results of this review should prove helpful to further illuminate the effects of estrogen on the therapeutic efficacy of anticancer drugs and to develop future drug treatment strategies based on ESR status to achieve optimal outcomes.