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.

Current State of Breast Cancer Diagnosis, Treatment, and Theranostics

“…LH-RH agonists act by pituitary desensitization and receptor downregulation, thereby suppressing gonadotrophin release. LH-RH exerts direct anticancer activity on malignant tissue that is independent from the suppression of the ovarian steroid synthesis and secretion [ 145 , 146 ]. Fulvestrant, a selective estrogen receptor degrader (SERD), is another drug that is suitable for breast cancer patients refractory to previous hormonal therapy.…”

Nanoparticles Targeting Receptors on Breast Cancer for Efficient Delivery of Chemotherapeutics

“…Produced in the hypothalamus, luteinizing hormone releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) triggers the release of steroid sex hormones, estrogen, progesterone, and testosterone [ 155 ]. These steroid hormones promote the growth of breast cancer cells.…”

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…Aromatase (CYP19A1) is the enzyme responsible for synthesizing estrogen from androgen precursors [529]. Aromatase inhibitors and gonadotropin releasing hormone agonists suppress estrogen production and are often prescribed as adjuvant therapy to post-menopausal patients [530][531][532]. The ESR1 D538G, Y537S/C/N, and to a lesser degree L536H/R activating mutations also appear in aromatase inhibitor treated patients ( Figure 5B, Supplementary Table S5) [529,[533][534][535].…”