The expression of GHRH and its receptors in breast carcinomas with apocrine differentiation—further evidence of the presence of a GHRH pathway in these tumors

Abstract

Apocrine breast carcinomas were evaluated for the expression of components of the growth hormone-releasing hormone (GHRH) autocrine/paracrine pathway: GHRH and its receptors (GHRH-R), as mammary apocrine carcinomas and epithelium seemed to be uniformly positive for GHRH-R in a pilot study. The apocrine phenotype was determined on the basis of hematoxylin-eosin morphology and a congruent immunohistochemical profile (estrogen receptor negativity, androgen receptor and gross cystic disease fluid protein-15 positivity). Thirty-five formalin-fixed, paraffin-embedded apocrine breast cancers in tissue microarrays and 24 cases using whole-tissue sections were evaluated for GHRH-R and GHRH expression by immunohistochemistry using polyclonal antibodies raised against various domains of GHRH-R and one polyclonal antibody specific for GHRH. GHRH-R positivity was detected in the overwhelming majority (ranging from 90% to 100%) of apocrine breast carcinomas with all but one of the antibodies applied. The expression was usually diffuse with only isolated cases showing positivity in less than 50% of tumor cells. With the PA5-33583 antibody, GHRH-R positivity was seen only in 73% of the cases in at least 50% of the tumor cells. GHRH expression was also present in all but one case tested, with more than 50% of the cells expressing it in 30/34 cases. These results support a high rate of GHRH-R and GHRH expression in apocrine breast carcinomas. Whether these findings can be exploited for the targeted treatment of apocrine breast carcinomas with GHRH antagonists requires further study.

Expression of growth hormone-releasing hormone receptors in apocrine adnexal tumours and apocrine glands of the skin

“…To reduce the possibility of non-specific or false staining, we selected two primary GHRH-R antibodies, which were designed to recognise different domains of the GHRH-R protein. Our results on breast carcinomas [5,6] and from this limited series of rare apocrine skin adnexal lesions and representative examples of normal apocrine structures suggest that GHRH-R expression is a relatively uniform, although not fully specific, feature of normal and neoplastic apocrine epithelium.…”

“…Although apocrine (oxyphilic) differentiation can be recognised on haematoxylin and eosin-stained slides in most cases, sometimes ancillary studies are useful for verification. According to our previous findings, GHRH-R is almost universally expressed in apocrine lesions of the breast [5,6]. Encouraged by this finding, we analysed the GHRH-R expression of normal cutaneous (anogenital and axillary) apocrine glands and a small series of cutaneous sweat gland neoplasms with apocrine differentiation.…”

“…The ab76263 and PA5-33582 antibodies recognise the C-terminal (fourth cytoplasmic) and the N-terminal (first extracellular) domains of the GHRH-R protein, respectively. A 10% cut-off was used to define positive staining with the GHRH-R antibodies, as previously described [5,6]. Normal cadaver pituitary tissue was used as positive control, and the specimens were evaluated only in the case of adequate positivity.…”

“…Growth hormone-releasing hormone (GHRH) and its receptors (GHRH-R) have been implicated in carcinogenesis both by means of a classical endocrine mechanism mediated by growth hormone-induced release of insulin-like growth factor from the liver, and as autocrine/paracrine mechanism [3,4]. In a previous IHC-based study, we identified GHRH-Rs to be rather uniformly present in apocrine metaplasia and carcinomas of the breast [5,6]. The morphological similarity of mammary apocrine metaplasia, apocrine breast carcinomas, and adnexal tumours demonstrating apocrine differentiation (oxyphilic metaplasia) prompted us to test for the presence of GHRH-R in the latter.…”

Apocrine Encapsulated Papillary Carcinoma of the Breast: The First Reported Case with an Infiltrative Component

“…This subset of breast tumors is generally estrogen receptor (ER) negative, progesterone receptor (PR) negative, and androgen receptor (AR) positive [ 6 ]. Our previous results suggest that these tumors are also almost uniformly positive for growth hormone-releasing hormone-receptor (GHRH-R) [ 7 8 ]. The majority of apocrine carcinomas can be considered special variants of NST carcinomas, although apocrine differentiation has also been reported in several special-type cancers, including EPC [ 9 10 11 12 ].…”