PTTG expression in different experimental and human prolactinomas in relation to dopaminergic control of lactotropes

CRISTINA C; DIAZ TORGA G; GOYA RG; KAKAR SS; PEREZ MILLAN MI; GIANNELLA NETO D; BRONSTEIN MD; BECU VILLALOBOS D

Molecular Cancer

BMC

Lugar: Inglaterra; Año: 2007 vol. 6 p. 4 - 9

Pituitary tumors rarely produce metastasis, but cause considerable morbility and mortality. Among them, prolactinomas account for approximately 30% of intracranial tumors. They are usually benign, and can be effectively treated with dopaminergic agents. Nevertheless, 15% of these may become resistant to classical pharmacological therapy, are invasive and aggressive, and require extirpation. In general, pituitary tumors result from monoclonal growth and intrinsic genetic defects which are related to oncogenes, suppressor genes, and from genes responsible of differentiation (Shimon & Melmed 1997).  On the other hand, growth factors of hypothalamic or pituitary origin may act on aberrant cells, contributing to their proliferation. Point mutations identified up to date can only account for a small percentage of pituitary tumors, and the mechanism of pituitary tumorigenesis is still unraveling. Pituitary tumor transforming gene (pttg) has been proposed as an important paracrine growth factor involved in early pituitary tumorigenesis. It has been reported to be involved in lactotroph transformation and onset of angiogenesis in estrogen-treated rats (Heaney et al. 1999), and its expression is high in prolactinomas (Zhang et al. 1999). Pttg is a recently cloned oncogene that was identified in rat pituitary tumor cells by differential mRNA display (Pei & Melmed 1997).  PTTG (protein encoded by pttg) has been recognized as a mammalian securin protein that maintains binding of sister chromatides during mitosis (Zou et al. 1999). PTTG must be proteolysed during cell division for sister chromatid separation to occur, and failure of this elicits inappropriate sister chromatid exchange, resulting in genetic instability as an early tumorigenic event (Yu & Melmed 2004). Several lines of evidence support the role of PTTG in tumorigenesis (Yu & Melmed 2004).  Overexpressed PTTG induces cell aneuploidy, transforms NIH3T3 cells in vitro and in vivo, stimulates basic fibroblast growth factor (FGF-2) production, and stimulates proliferation and angiogenesis. Furthermore PTTG transactivates the oncogene c-myc, which in turn may influence cell growth (Yu & Melmed 2004). PTTG is expressed in high levels in different pituitary tumors (Zhang et al. 1999) and other neoplasms including carcinomas of lung, breast, colon, thyroid, adrenal, liver, kidney, endometrium, uterus, ovary  leukaemia and lymphomas (Hamid & Kakar 2003). The expression of PTTG in normal tissues is restricted, with highest expression in the testis. The role of PTTG on prolactinomas is not clear, and controversy exists as to whether it is increased in these adenomas. We sought to determine the level of PTTG expression in three different experimental models of lactotroph hyperplasia: the dopaminergic D2R knockout female mouse (Diaz-Torga et al. 2002), the estrogen-treated rat (Diaz-Torga et al. 1998), and the senescent female rat (Goya et al. 1991). These three models share the characteristics of hyperprolactinemia and reduced dopaminergic action at the pituitary level (Sarkar et al. 1982; Kelly et al. 1997; Herenu et al. 2006; Sanchez et al. 2003) . We also studied samples from human dopamine resistant prolactinomas. We believe that the elucidation of the factors involved in the regulation of lactotr