Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells

Abstract

The oncogenic effects of epidermal growth factor (EGF) have long been established. EGF receptor (EGFr) is overexpressed in many types of tumors and constitutes a target for cancer treatment. The pituitary gland is a target of EGF action and it is very likely that EGFr plays a role in pituitary tumor formation and progression. However, there is a controversy in the literature concerning EGFr expression in the different types of pituitary adenomas. In the present study we investigated the expression pattern of the wild type EGFr (EGFrWT) and the constitutively active variant III (EGFrvIII) at the mRNA and protein levels in a large series of pituitary tumors. EGFrWT was found in a high percentage of hormone-secreting tumors, but only in a small fraction of non-functioning pituitary adenomas, while no expression of the EGFrvIII could be detected by nested RT-PCR in any tumor. Among the hormone-secreting adenomas, the highest incidence of EGFr expression was found in Cushing's pituitary adenomas. Furthermore, immunohistochemistry for the phosphorylated EGFr revealed the presence of activated EGFr in most Cushing's adenomas, compared with most pituitary adenomas. Taking into account that downregulation of p27/Kip1 plays a significant role in corticotrope tumorigenesis and that EGFr mitogenic signaling results in decreased p27/Kip1, we searched for a correlation between EGFr expression and p27/Kip1 levels in corticotropinomas. Low p27/Kip1 immunoreactivity was observed in corticotropinomas expressing EGFr. On the other hand, somatotropinomas expressing EGFr had high p27/Kip1 immunoreactivity. These data suggest a corticotrope-specific phenomenon and indicate that EGFr may have a role in the unbalanced growth of corticotrope tumoral cells.

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

“…EGF binding was detected in pituitary tumors, despite the initial negative autoradiography results (41,44,45). Semiquantitative reverse transcriptase PCR analysis and northern blot showed EGFR transcript in representatives of all pituitary tumor types, including all the assayed corticotrophinomas (38,41). In contrast, all tumors were negative for the constitutive active truncated EGFR variant III (41).…”

“…Semiquantitative reverse transcriptase PCR analysis and northern blot showed EGFR transcript in representatives of all pituitary tumor types, including all the assayed corticotrophinomas (38,41). In contrast, all tumors were negative for the constitutive active truncated EGFR variant III (41). Initial immunohistochemical analysis revealed EGF and its receptor, as detected by two MABs against the cytoplasmatic (clone F4) and extracellular (clone 29.1) EGFR domains, mainly in the majority of the nonfunctioning pituitary adenomas in a set of 54 pituitary adenomas (42).…”

“…A MAB against the intracellular domain (E3138) revealed EGFR expression in corticotrophs as well as in other pituitary cell subpopulations (36). In human pituitary autopsies, EGFR immunoreactivity was mainly detected in corticotrophs and lactotrophs using antibodies directed against the intracellular (clone F4) and extracellular (clone E30) domains (39,41).…”

“…However, it soon became evident that EGF is present in human corticotrophinomas and tends to correlate with invasiveness (39,43). EGF binding was detected in pituitary tumors, despite the initial negative autoradiography results (41,44,45). Semiquantitative reverse transcriptase PCR analysis and northern blot showed EGFR transcript in representatives of all pituitary tumor types, including all the assayed corticotrophinomas (38,41).…”

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

“…Overexpression of p27 leads to cell-cycle arrest (7), while lack of p27 results in pituitary adenomas in p27 'knockout' animals (8)(9)(10). We, and others, have previously shown reduced expression of p27 in a variety of pituitary adenomas (11)(12)(13)(14)(15), although a single study was not able to confirm this (16).…”