Treatment of Breast Cancer With Gonadotropin-Releasing Hormone Analogs

Abstract

Although significant progress has been made in the implementation of new breast cancer treatments over the last three decades, this neoplasm annually continues to show high worldwide rates of morbidity and mortality. In consequence, the search for novel therapies with greater effectiveness and specificity has not come to a stop. Among the alternative therapeutic targets, the human gonadotropin-releasing hormone type I and type II (hGnRH-I and hGnRH-II, respectively) and its receptor, the human gonadotropin-releasing hormone receptor type I (hGnRHR-I), have shown to be powerful therapeutic targets to decrease the adverse effects of this disease. In the present review, we describe how the administration of GnRH analogs is able to reduce circulating concentrations of estrogen in premenopausal women through their action on the hypothalamus-pituitary-ovarian axis, consequently reducing the growth of breast tumors and disease recurrence. Also, it has been mentioned that, regardless of the suppression of synthesis and secretion of ovarian steroids, GnRH agonists exert direct anticancer action, such as the reduction of tumor growth and cell invasion. In addition, we discuss the effects on breast cancer of the hGnRH-I and hGnRH-II agonist and antagonist, non-peptide GnRH antagonists, and cytotoxic analogs of GnRH and their implication as novel adjuvant therapies as antitumor agents for reducing the adverse effects of breast cancer. In conclusion, we suggest that the hGnRH/hGnRHR system is a promising target for pharmaceutical development in the treatment of breast cancer, especially for the treatment of advanced states of this disease.

Keywords: GnRH agonist; GnRH analogs; GnRH antagonist; breast cancer; breast cancer adjuvant therapy; gonadotropin-releasing hormone (GnRH); gonadotropin-releasing hormone receptor (GnRHR).

Figure 1

Activation of GnRHR in gonadotropic cells. GnRH is produced in hypothalamus and released in a pulsatile fashion to act primarily on the anterior pituitary. Here, the GnRHR is expressed in the membrane of gonadotropic cells (gonadotropes). Receptor activation stimulates the synthesis and secretion of LH and FSH. In gonads, gonadotropins trigger gametogenesis as well as the synthesis and release of steroid sex hormones (estrogen, progesterone, and testosterone). In sex-steroid-dependent BC tumors, sexual hormones promote the tumoral growth. In BC tumors that express GnRHR, analogs of GnRH could improve the treatments anticancer by the inhibition of tumoral growth. Activation ().

Figure 2

Use of GnRH analogs as adjuvant therapy against breast cancer. GnRH antagonists () and non-peptide GnRH antagonists () are able to reduce FSH and LH expression by direct inhibition of GnRHR in gonadotropic cells. GnRH agonists () and cytotoxic analogs of GnRH () are able to reduce gonadotropin hormones levels after GnRHR desensitization in gonadotropic cells. Suppression of FSH and LH evoke diminution of estrogen, progesterone, and testosterone levels and the subsequent inhibition of growth in dependent sex-steroid tumors. Likewise, GnRH agonists (), GnRH antagonists (), and cytotoxic analogs of GnRHR () have direct antitumor effects over cancer cells, promoting in those the inhibition of cell growth. The systemic and local effect of GnRH analogs could improve the clinical response in BC patients, principally those that are treated with combined therapies. Inhibition (⊥), desensitization (−).