Somatostatin and Growth Hormone-Releasing Hormone in Normal and Tumoral Human Breast Tissue: Endogenous Content, in Vitro Pulsatile Release, and Regulation

Abstract

Endogenous production of SRIH and GHRH was analyzed in human breast tissue. SRIH precursor (pro-SRIH) was identified after Sephadex G-50 filtration of acetic acid extracts of normal and tumoral human breast samples. SRIH-(1-14) or -(1-28) could not be detected in breast tissue, whereas the immunoreactive SRIH released in vitro was characterized as SRIH-(1-28). Endogenous production of GHRH was assessed by identification of GHRH messenger ribonucleic acid by PCR followed by sequencing of the amplified complementary DNA and by high performance liquid chromatographic characterization of immunoreactive GHRH contained in the tissue and released in vitro. There were no differences in pro-SRIH or GHRH-(1-44) tissue contents between normal and tumoral samples. The release of both peptides was evidenced in perifusion and static incubation. Perifusion of normal breast tissue (n = 3) showed pulsatile release of SRIH and GHRH. Perifusion of tumors (n = 4) showed SRIH release in 50% of the cases. SRIH release was pulsatile in one case. GHRH release was observed in the four tumoral samples analyzed, but was pulsatile in only one case. In static incubation, tumors (n = 6) secreted 13 times more GHRH than did normal samples (n = 3; 383 +/- 92 vs. 29.6 +/- 4.6 fmol/mg protein; P < 0.05). Stimulation of GHRH release by exogenous SRIH was observed only with the normal tissue. Together these data provide evidence for the existence of local production of SRIH and GHRH by human breast. Hypersecretion of GHRH by breast tumors indicates that this peptide could play a role in maintaining epithelial cell proliferation as is the case for other peptides produced locally.

Inhibition of growth, production of insulin-like growth factor-II (IGF-II), and expression of IGF-II mRNA of human cancer cell lines by antagonistic analogs of growth hormone-releasing hormone in vitro

“…However, the mechanism of action of GHRH antagonists remains to be clarified. It was shown that several human cancers and cancer cell lines produce GHRH (34,35,39). GHRH-sensitive receptors on various tumor cells have been also described (19).…”

“…Besides the hypothalamus, GHRH also is produced in various peripheral tissues including tumors (34,35). The receptors for GHRH also were detected in various extrapituitary organs (36).…”

Isolation and sequencing of cDNAs for splice variants of growth hormone-releasing hormone receptors from human cancers

“…However various studies indicate that GHRH, in addition to stimulating the release of growth hormone from the pituitary, functions as an autocrine͞paracrine growth factor in human breast, ovarian, and endometrial cancers and SCLC (1,8,48,49). Thus the expression of mRNA for GHRH and the presence of biologically active GHRH were observed in human breast, endometrial, and ovarian cancers (48,49). Similarly, H-69 and H-510A SCLC lines express mRNA for GHRH that apparently is translated into peptide GHRH and then secreted by the cells (8).…”

The expression of growth hormone-releasing hormone (GHRH) and splice variants of its receptor in human gastroenteropancreatic carcinomas

“…Thus, the presence of SV 1 has been shown in MIA PaCa-2 human pancreatic cancer, in some human prostatic, renal, ovarian, breast, lung, and bone cancer lines (3,18,(23)(24)(25)(26)(27)(28)(29), as well as in primary specimens of human prostate cancer (30). Furthermore, the endogenous production of GHRH was detected in diverse human cancers such as endometrial, ovarian, breast, prostatic, pancreatic, gastric, colon cancers, SCLC, and sarcomas (21,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). The proliferation of SCLC, sarcomas, and breast cancer cells can be stimulated by administration of GHRH or its agonistic analogs and conversely inhibited by GHRH antagonists.…”