Expression of GHRH-R in primary and metastatic mammary carcinomas.

Abstract

19 Background: In addition to its nominative function, as a neurohormone acting on the pituitary, Growth Hormone Releasing Hormone (GHRH) has been shown to modify the growth behavior of numerous cancers, including breast. GHRH is produced by tumor cells, acts in an autocrine/paracrine manner, and requires the presence of GHRH receptor (GHRH-R) on the tumor cells to exert its effects. As this work has been done predominantly on tumor cell lines and xenografts, we set out to examine the clinical analog. Methods: Matched primary and metachronous metastases from 50 breast cancers were included in this study of GHRH-R in breast cancer. Immunohistochemistry for GHRH-R (AbCam) was performed on paraffin sections and the staining results were assessed semi quantitatively from 0 (negative) to 3+ (strongly positive). A section from normal pituitary was use as positive control. Results: Forty-three of the primary breast cancers (86%) that ultimately relapsed or metastasized showed moderate to strong immunohistochemical expression of GHRH-R. Tumors from the metastatic foci also showed strong immunoreactivity in 78%, 71%, and 44% of liver, brain, and bone foci, respectively. The lower intensity of staining in bone samples may be due to the effect of the decalcification process routinely performed before staining. Whenever present, the non-neoplastic glands adjacent to breast tumors showed either negative or 1+ reaction for GHRH-R. The study population will be expanded to 100 patients, and the GHRH-R IHC results will be correlated with HER2, ER status, and clinical outcome. Conclusions: We conclude that the great majority of mammary carcinomas at primary and metastatic sites express GHRH-R. This finding could potentially serve as a basis for therapeutic approaches using peptide receptor antagonists. By receptor blockage using receptor antagonists, with minimal pharmacologic side effects, we have been able to control the growth in a number of tumor cell lines (HCC1806, MDAMB468, MDAMB435S, MCF7, T47D, HCC1937, BT474, and MX1s). Based on the presence of GHRH receptors in these clinical tumors, we conclude that clinical trials evaluating GHRH recpeptor antagonists are indicated.