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

Nature Medicine volume 5, pages 1317–1321 (1999)Cite this article

Abstract

Pituitary tumors are commonly encountered, and result from clonal expansion of a single mutated cell1. Hypothalamic hormones, local growth factors and circulating sex steroid hormones promote pituitary tumor growth and expansion into large invasive tumors2. Estrogen acting directly through its receptor and by stimulation of fibroblast growth factor regulates prolactin synthesis and secretion3,4. Fibroblast growth factor-2 (bFGF) modulates angiogenesis, tumor formation and progression in many tissues, including the anterior pituitary5,6,7,8. A pituitary tumor-derived transforming gene (PTTG) has been isolated, which is tumorigenic in vivo, regulates bFGF secretion, and inhibits chromatid separation9,10,11. The human PTTG family consists of at least three homologous genes, of which PTTG1 is located on chromosome 5q3312 and is expressed at low levels in most normal human tissues but is highly expressed in malignant human cell lines and in pituitary tumors13. 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.

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Figure 1: In vivo estrogen-induction of PTTG in rat lactotroph tumors.
Figure 2: Early estrogen-induction and concordant expression of pituitary bFGF, PTTG and VEGF.
Figure 3: Regulation of pttg in vitro by estrogen and bFGF.

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Acknowledgements

We thank L. Chen and M. Perone for technical support. This work was supported by NIH grant CA75979 (S.M.); a Fulbright Research Scholarship; The Sir Samuel Leonard Simpson Fellowship; and an Endocrine Foundation Fellowship (A.P.H.).

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Authors and Affiliations

  1. Department of Medicine, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, 90048, California, USA

    Anthony P. Heaney, Gregory A. Horwitz, Zhiyong Wang & Shlomo Melmed

  2. Departments of Pathology, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, 90048, California, USA

    Regina Singson

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Correspondence to Shlomo Melmed.

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Heaney, A., Horwitz, G., Wang, Z. et al. Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nat Med 5, 1317–1321 (1999). https://doi.org/10.1038/15275

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