KiSS1/GPR54 and estrogen-related gene expression profiles in primary breast cancer

Abstract

Abstract. The estrogen receptor α (ERα)-mediated pathway plays a critical role in breast cancer development and progression. KiSS1 was previously described as a metastasis suppressor gene in certain carcinomas. However, the role of KiSS1/GPR54 in breast cancer remains controversial. Whether the function of the KiSS1/GPR54 system depends on estrogen signaling in the breast cancer cell remains to be determined. This study aimed to determine the expression profiles of the KiSS1/GPR54, ERα, ERβ, aromatase and cyclin D1 genes in human breast cancer tissues, and to identify a possible link between the expression levels of the studied genes and the selected clinical and pathological features. The study subjects comprised 59 females treated surgically for primary breast cancer. Total RNA was extracted from frozen breast cancer tissues, and expression levels were examined to determine any correlations. We observed strong positive correlations between the expression levels of the studied genes. The expression of ERα correlated positively with progesterone receptors (PRs), and in these tumors we also observed positive correlations between KiSS1, GPR54 and cyclin D1 mRNAs and the ERα protein. ER-positive breast tumors exhibited higher KiSS1 and GPR54 levels than the ER-negative tumors. The expression levels of the ERα and GPR54 transcripts were higher in the moderately differentiated tumors (G2) compared to the poorly differentiated high-grade (G3) cancers. We also found that HER-2/neu status in breast cancer is negatively associated with GPR54 mRNA expression. Decreasing GPR54 mRNA expression levels in HER-2/neu (+) tumors may be associated with the deregulation of the classical estrogenmediated signaling pathway in breast tumors, and therefore, with promotion of tumor invasiveness. Our findings indicate that genes involved in the KiSS1/GPR54 system, as well as in the estrogen signaling pathway, may be utilizable molecular factors in pathogenesis studies of breast cancer.

Kisspeptin/KISS1R System in Breast Cancer

“…In contrast to this study, Jarzabek and others reported that ER-positive tumors exhibited higher KISS1 and KISS1R levels than ER-negative tumors50. This study also revealed that KISS1R expression is negatively associated with HER2 status in breast cancer50. Thus the expression profile and roles of KISS1 and KISS1R in breast cancer has been difficult to discern and this might simply reflect the great heterogeneity among breast tissue, in addition to the fact that mRNA levels may not necessarily correlate to protein levels.…”

“…They reported that KISS1 mRNA levels were high in breast tumors, compared to normal mammary tissue, whereas KISS1R mRNA levels were high in invasive tumors compared to normal tissue78. In contrast to this study, Jarzabek and others reported that ER-positive tumors exhibited higher KISS1 and KISS1R levels than ER-negative tumors50. This study also revealed that KISS1R expression is negatively associated with HER2 status in breast cancer50.…”

KiSS1 inhibits growth and invasion of osteosarcoma cells through inhibition of the MAPK pathway

“… 19 Some studies reveal that KiSS1 mRNA expression is also markedly reduced in tissues of breast cancer, 20 while other ones show that KiSS1 is highly expressed in estrogen receptor (ER)-positive breast tumors compared to the ER-negative tumors. 21 KiSS1 expression levels are found to be decreased in OS cell lines with increasing aggressiveness, while increases in human OS tissues and correlates with the metastasis of OS. 22 Differently from the study of Wang et al, 22 we found in the present study that KiSS1 was proved to be decreased in the nucleus and cytoplasm of human OS tissues compared to the ANCT, suggesting that loss of KiSS1 expression might be involved in the development of OS.…”

Controversial Role of Kisspeptins/KiSS-1R Signaling System in Tumor Development

“…They showed that in ERα-positive primary tumors, KiSS-1 levels are lower than ERα-negative tumors ( 22 , 23 ). In contrast, Jarzabek and colleagues demonstrated that ERα-positive breast tumors express higher levels of both KiSS-1 and KiSS-1R than ERα-negative tumors ( 24 ).…”