The Role of the Androgen Receptor Signaling in Breast Malignancies

Abstract

Abstract. Breast cancer (BrCa) is the most common malignancy among women worldwide, and one of the leading causes of cancer-related deaths in females. Despite the development of novel therapeutic modalities, triple-negative breast cancer (TNBC) remains an incurable disease. Androgen receptor (AR) is widely expressed inBreast cancer (BrCa) is the most common solid tumor among women with an annual incidence of 123 new cases/100,000 females according to the United States Cancer Statistics and 252.710 estimated new cases in the U.S. in 2017. Despite significant progress made in therapeutics during the last 2 decades, BrCa still has a poor prognosis with 5-year survival rates of metastatic disease reaching to 26% only. BrCa is the second leading cause of death among female cancers with 40,610 estimated deaths in the U.S. expected in 2017 (1).Breast cancer comprises a heterogeneous group of diseases with variable course and outcome. Currently, BrCa is subclassified into distinct molecular subtypes named: normal breast like, luminal A/B, HER-2 related, basal-like and claudinlow (2, 3). Estrogen receptor (ER), progesterone receptor (PR) and HER2 have long been established as useful prognostic and predictive biomarkers. Hormonal therapy in ER and PR positive tumors (4), as well as the use of monoclonal antibodies in HER2 over-expressing tumors (5) have shown promising results, however overall survival of metastatic disease remains relatively low (1). To date, androgen receptor (AR) has been suggested to play a key role in breast cancer biology in certain disease subgroups (6, 7).AR is expressed in all stages of breast cancer (in-situ, primary and metastatic disease) and its contribution to the progression of disease may differ depending on the stage (8). Overall, AR expression among patients with breast cancer has been estimated at approximately 77% and varies significantly among molecular subtypes of BrCa (9). Human observational studies have associated AR with better outcome in ER + tumors, but this positive effect may be lost in ER-tumors (10, 11). Of interest, AR expression correlates with better clinicopathological features in the most aggressive form of BrCa, triple-negative breast cancer (TNBC) (12). AR seems to have distinct roles in disease development and progression depending on the tumor's hormonal environment and specifically upon relative levels of androgens and estrogens.The historically used androgens together with antiandrogens, Selective AR Modulators (SARMs) and Androgen Receptor antagonists constitute valuable options for the treatment of specific disease subpopulations. In the past decade, a wealth body of studies have focused on AR targeting along with hampering major signaling pathways 6533 This Αrticle is freely accessible online.

Androgen Receptor in Breast Cancer: From Bench to Bedside

“…However, among the androgens, only testosterone (T) and dihydrotestosterone (DHT) can bind the AR ( 15 , 16 ). In the breast tissue, T is converted either to DHT by 5α-reductase or to 17β-estradiol (E2) by aromatase ( 17 ). Interestingly, DHT concentrations were significantly (3-fold) higher, whereas 5α-reductase levels were elevated 4- to 8-fold in breast carcinoma tissues compared with those in non-neoplastic breast tissues ( 16 ).…”

“…Interestingly, DHT concentrations were significantly (3-fold) higher, whereas 5α-reductase levels were elevated 4- to 8-fold in breast carcinoma tissues compared with those in non-neoplastic breast tissues ( 16 ). Of note, T is converted into estradiol only when the estrogen levels are very low ( 15 , 17 ).…”

Distribution and characteristics of androgen receptor (AR) in breast cancer among women in Addis Ababa, Ethiopia: A cross sectional study

“…AR is expressed in all stages of breast cancer (in-situ, primary and metastatic disease) [13] and several studies show AR may play different prognostic role in ER-positive and ER-negative breast cancers [7,8,14]. In ER-positive breast cancer, AR was reported to predict favorable disease outcome consistently.…”

“…Preclinical and clinical studies conducted in recent years are supporting the role of AR-targeting treatment in the management of breast cancer [9,13,16,19]. Therefore, both AR antagonists and AR agonists will likely become useful and safe options of treatment in various breast cancer subtypes particularly in combination with other agents already proved to be beneficial in treating breast cancer, but only the ongoing and future prospective clinical trials will allow us to establish which agents are the best options in every specific condition [8,9,13,16,[20][21][22].…”

Androgen Receptor Expression and Its Correlation with Clinicopathological Parameters in Iranian Patients with Triple Negative Breast Cancer

“…The AR role for stimulation of the cancer cells growth and its potential therapeutic significance was revealed first in the prostate cancer. Recently, some studies identified AR ability for acceleration of the breast cancer growth ( 18 , 19 ). High proportion of breast tumors express AR ( 20 , 21 ).…”