The genes for gonadotropin-releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer

Abstract

While gonadotropin-releasing hormone (GnRH) or GnRH receptor (GnRHR) have been reported to exist in tissues other than brain and pituitary, there is no report concerning co-expression of GnRH and GnRHR in human breast tissues. To address this question, we have examined whether mRNA for GnRH as well as GnRHR was present in different human breast samples, by employing the reverse transcriptionpolymerase chain reaction (RT-PCR) protocol followed by Southern blotting of the PCR products. Coexpression of GnRH and GnRHR genes was further confirmed by dot blot hybridization using appropriate [ 32 P]-labeled probes. We thus tested fibrocystic breast (4 cases), invasive ductal carcinomas (6 cases) and 1 adjacent non-neoplastic tissue. GnRHR and GnRH mRNAs were found in all actin-positive samples including malignant as well as nonmalignant tissues. Quantitative determinations of mRNA did not reveal significant differences between malignant and non-malignant breast samples for either GnRH or GnRHR gene expression. Our data show that neither gene was overexpressed in the breast cancer samples compared with normal breast tissue. Since GnRH agonists inhibit breast epithelial cell growth, the presence of GnRHR mRNA suggests that GnRH may specifically affect breast cell growth. Our data thus raise the possibility of an autocrine/paracrine role for GnRH in human mammary gland. Int. J. Cancer 71:595-599, 1997.r 1997 Wiley-Liss, Inc.Gonadotropin-releasing hormone (GnRH) is a decapeptide that stimulates, via a high-affinity membrane receptor (GnRHR), the synthesis and release of pituitary gonadotropin luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn promote development of gonadal functions (Clayton and Catt, 1981). The human GnRHR consists of 328 amino acids characterized by 7 transmembrane domains, a common feature of all G-protein-coupled receptors (Kakar et al., 1992).The existence of extra-pituitary GnRHR sites in humans is controversial. Northern blot analysis failed to detect GnRHR mRNAs in any of the non-pituitary tissues examined (Kakar et al., 1992). However, using a reverse transcriptase-polymerase chain reaction (RT-PCR) protocol, these mRNAs have been detected in granulosa-luteal cells (Peng et al., 1994) and in gynecological tumors including endometrial (Chatzaki et al., 1996) and ovarian tumors (Imai et al., 1994), as they were in breast and in prostate tumors (Kakar et al., 1994).The rationale for the chronic administration of potent GnRH analogs (GnRH-A) in therapy for hormone-dependent premenopausal breast cancer is based on the observed suppression of ovarian estrogen production resulting from the desensitization of the pituitary gland. In addition, evidence is accumulating that GnRH-A may also exert direct antiproliferative effects on breast cell lines via specific binding sites (Eidne et al., 1985(Eidne et al., , 1987Miller et al., 1985). This possibility has been strengthened by the identification by RT-PCR of mRNA for GnRHR in breast tissues (Kakar et al., 1994).The study of GnRH ...

Down-regulation of proliferation and up-regulation of apoptosis by gonadotropin-releasing hormone agonist in cultured uterine leiomyoma cells

“…The prerequisite for direct action of GnRHa in peripheral tissues is the presence of GnRH receptors in target cells. It is evident that there are GnRH receptors and GnRH-binding sites in many kinds of extrapituitary tissues including leiomyoma (1,12,21,22). Our data indicating that GnRH receptor mRNA is expressed in cultured leiomyoma cells support the above notion, which indicates a direct GnRHa action in leiomyoma cells.…”

“…Gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of pituitary gonadotropin luteinizing hormone (LH) and follicle-stimulating hormone (FSH) via a high-affinity membrane receptor (GnRH receptor) which, in turn, promotes the development of gonadal function (1). Continuous administration of GnRH agonists (GnRHa), by downregulating the number and sensitivity of GnRH receptors, suppresses pituitary gonadotropin biosynthesis and release, which leads to a decrease in estrogen and progesterone secretion from the ovary (2,3).…”

Gonadotropin-releasing hormone neuropeptides and receptor in human breast cancer: Correlation to poor prognosis parameters

“…Transcript levels showed no statistically significant differences between malignant and benign biopsies for either gene. This is in accordance with previous findings of semi-quantitative determinations of GnRH I mRNA in a small number of tissues [19]. Chen et al, 2002 [5] however, reported higher levels of GnRH I and GnRH II in the malignant biopsies of breast in comparison with the adjacent benign tissue, as detected in 6 breast cancer patients by semi-quantitative RT-PCR, attributed to the overall high protein expression and enhanced transcription machinery that exist in cancer cells.…”

Biology of the gonadotropin-releasing hormone system in gynecological cancers

“…Kottler et al (42) demonstrated co-expression of GnRH and its receptor in malignant and non-malignant tissues of the human breast. As GnRH agonists inhibit breast epithelial cell growth, these data raise the possibility of an autocrine/paracrine role for GnRH in the human mammary gland (42).…”