Deepening on Breast Cancer Metastasis: The ERα-Mediated Modulation of KISS/KISS1R System

Abstract

Breast cancer is one of the most important diseases worldwide with an annual global fatality of almost 800 000 and the primary cause of cancer mortality in women (1). The risk of breast cancer is age dependent. The probability of developing breast cancer is equal to 0.04% per year for average risk women between age 30 and 39 and increases to more than 10% per year in those over 80 years (2). Breast cancer in women under 40 years is not a common condition. However, a dramatic increase in the number of breast cancers diagnosed in premenopausal women has been reported in several countries. In the United States, 5.5% of breast cancers occur in women younger than the age of 40 years. Approximately 1 in 40 women diagnosed with early breast cancer is very young ( 35 y). Breast cancer in young women is associated with a positive family history and gene mutations more frequently than in older women (3). However, the mainly cause of deaths is not the primary tumors itself but also the result of metastasis to others organs (4). The biological mechanisms of metastasis development have been studied for more than 100 years. However, knowledge of all the cellular and molecular mechanisms that trigger it is still unclear. Further research is necessary to better understand this process, discover solutions for its prevention, and provide patients with a longer life expectancy. The steps involved in the process of metastasis are often described as the “metastatic cascade,” where single tumor cells or small tumor cell aggregates first detach and leave the primary tumor; next, the cells infiltrate the surrounding stroma (invasion) and enter into the circulatory system (intravasation); and finally, they travel to distinct sites where they establish secondary tumor growth (extravasation) (5–9). This seemingly simple process is one of the main concerns of current biomedical science, so when an interesting finding providing hope is encountered, nature itself appears to be illustrating its inherent complexity. In this difficult path toward understanding this complex process, Cvetkovic et al (10) have opened a new door that will give rise to new research in the near future. They have focused their research in Kisspeptin receptor (KISS1R), also known as GPR54. This is a G protein-coupled receptor that binds kisspeptins (Kps). Kps are neuropeptides encoded by KISS1 and are the natural ligands of the KISS1R. These were initially described as metastasis inhibitors in melanoma (11). Later it was demonstrated that loss-of-function mutations in KISS1R cause absence of puberty and low LH and FSH levels in humans (12, 13). Therefore, the major role for the KISS/KISS1R system is to regulate the gonadotropic axis at puberty and during adulthood via tight modulation of GnRH secretion (14). KISS/KISS1R is also expressed outside of central nervous system and seems to play a pivotal role in metastatic pathways. Loss of KISS1 expression has also been correlated with increased metastasis and/or cancer progression in malignant pheochromocytoma (15), esophageal squamous cell carcinoma (16), bladder (17), ovarian (18), gastric (19), and pancreatic (20) tumors. Moreover, specific animal studies examining KISS1 in breast cancer clearly demonstrated suppression of metastases in vivo (11, 18, 21, 22). In contrast, Martin et al (23) found KISS1 messenger elevated in node-positive breast tumors in comparison with node-negative samples, yet no differences were observed in KISS1R, and other authors indicate that KISS1R signaling may correlate positively with breast tumor progression and metastatic potential (24, 25). A possible explanation for this paradox could be the associations of Kps