Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis

Abstract

Pituitary tumors are commonly encountered, and result from clonal expansion of a single mutated cell. Hypothalamic hormones, local growth factors and circulating sex steroid hormones promote pituitary tumor growth and expansion into large invasive tumors. Estrogen acting directly through its receptor and by stimulation of fibroblast growth factor regulates prolactin synthesis and secretion. Fibroblast growth factor-2 (bFGF) modulates angiogenesis, tumor formation and progression in many tissues, including the anterior pituitary. A pituitary tumor-derived transforming gene (PTTG) has been isolated, which is tumorigenic in vivo, regulates bFGF secretion, and inhibits chromatid separation. The human PTTG family consists of at least three homologous genes, of which PTTG1 is located on chromosome 5q33 and is expressed at low levels in most normal human tissues but is highly expressed in malignant human cell lines and in pituitary tumors. We report here that pituitary pttg is regulated in vivo and in vitro by estrogen. Maximal induction of rat pituitary pttg mRNA in vivo occurred early in pituitary transformation (normal cell to hypertrophic/hyperplastic cell), coincident with bFGF and vascular endothelial growth factor induction and pituitary angiogenesis. We also demonstrate that pttg expression is induced by bFGF, and show concordant pttg and bFGF expression in experimental and human pituitary adenomas. As bFGF and estrogen both induce pttg, and pttg expression coincides with the early lactotrophic hyperplastic response, angiogenesis and prolactinoma development, we propose a previously unknown paracrine growth factor-mediated mechanism for pituitary tumor pathogenesis and potentially other estrogen-regulated tumors.

Securin is overexpressed in breast cancer

“…Although we have not correlated securin expression with Ki-67 levels in these breast tumors our previous studies demonstrated that securin overexpression leads to increased proliferative rates, and mitogens such as estrogen and bFGF increased pituitary, thyroid and breast tumor securin levels. 13,15,24 We propose that our observed increased securin is a marker of breast tumor proliferative capacity and may aid in detection of cancers that are more likely to follow an aggressive clinical course, and the identification of patients that are more likely to benefit from adjuvant therapies. As securin overexpression disrupts normal sister chromatid separation leading to aneuploidy, an alternate explanation for increased securin expression in the breast tumors may be due to aneuploidy.…”

“…Protein lysates were prepared from the same subset (used for Northern blot analysis) of breast tissues using RIPA buffer, 15 soluble proteins (50 mg) separated by SDS-PAGE electrophoresis, transferred to PVDF membranes (Amersham), and incubated with antibodies to securin (1:5000), and b-actin (1:2500; Sigma). Blots were then washed and incubated with appropriate horse radish peroxidase-conjugated secondary antibodies.…”

“…fold-increase; grade 3; 4.171.3, Po0.05) (Figure 3b) compared to grade 1 pleomorphic tumors. Given our previous studies demonstrating estrogen-mediated pituitary securing induction 15 we also examined ER-a expression in the breast tumors. In all, 71 of 90 tumors exhibited immunohistochemical ER-a expression, and in most of these tumors concordant high securin and ER-a expression levels were observed (Figure 3c).…”

“…15 As pituitary and breast cellular proliferation are both hormone dependent, we examined securin expression in 90 breast tumors and 18 normal breast tissues.…”

Expression of Pituitary Tumor Transforming Gene 1 is an Independent Factor of Poor Prognosis in Localized or Locally Advanced Prostate Cancer Cases Receiving Hormone Therapy

“…PTTG1 expression can not only be androgen upregulated in castrated rat prostate and human prostate cancer cell LNCaP (Zhu et al, 2006), but also be induced by estrogen through an estrogen-response element in the PTTG1 promoter region in prolactinoma (Heaney et al, 1999). Androgen pathways and estrogen signaling all have been showed to play important roles in prostate cancer development and progression (Bonkhoff and Berges, 2009;Celhay et al, 2010).…”