The role of prolactin and growth hormone in breast cancer

Abstract

This review will focus on the role for prolactin (PRL) and growth hormone (GH) in mammary tumor formation. Much attention has previously been focused on circulating levels of GH/PRL in relation to mammary tumor formation. We will review data demonstrating that these ligands also could be produced locally in dierent organs, including the mammary gland and mammary tumors, and suggest that this local production may be of importance for pathological conditions. We will also discuss mechanisms for crosstalk between steroids and GH/PRL. A crosstalk between GH-and PRL response is possible at multiple levels. In the human, GH can activate both the prolactin receptor (PRLR) and the growth hormone receptor (GHR). We have demonstrated that activation of the PRLR, but not the GHR, is inducing mammary tumors in transgenic mice. Furthermore, the elevated levels of insulin-like growth factor 1 (IGF-I) seen in the GHR activating transgenic mice is not sucient for tumor induction. The induced tumors express functionally active prolactin that could be of importance for the tumor formation. Paracrine/aurocrine stimulation by PRL may be more important than PRL transported via the circulation. In women, the role for stimulation of the PRLR and/or the GHR in mammary tumor formation has not been proven, although experiments from primates suggest that the PRLR could be of importance.

Identification of molecular apocrine breast tumours by microarray analysis

“…Inhibition of HMGCR has been reported to inhibit growth of breast cancer cell lines through a reduction in geranylgeranylation of rhoA (Denoyelle et al, 2003). The apocrine tumours also express GHR, PRLR and EGFR, which can be inhibited using a variety of direct and indirect approaches (Santen et al, 1990;Fuh et al, 1992;Chen et al, 1999;Wennbo and Tornell, 2000;Paez et al, 2004). The potential therapeutic implications of identifying molecular apocrine tumours suggest that further studies to produce a more robust definition of the molecular apocrine profile and the mechanisms leading to its expression are justified.…”

Development of Pure Prolactin Receptor Antagonists

“…Similarly, introducing within the G129R-hPRL various combinations of mutations enhancing site 1 affinity (43) or decreasing site 2 affinity (A22W mutation) (32) failed to achieve the expected improvement of this antagonist. 2 In the course of a classical structure-function study aimed at characterizing the functional involvement of the N-terminal tail of hPRL, which is the region within the PRL/GH hormone family with the greatest sequence difference (27), we actually found that deletion of the first 9 amino acids slightly increases hormone activity, an effect presumably mediated by site 1 enhancement, whereas deletion of residues 1-14 decreases activity, presumably by affecting site 2 affinity (68). Thus, these N-terminal deletions were inserted into the G129R-hPRL analog because they were anticipated to improve the antagonistic properties of the latter either by increasing its site 1 affinity or by altering that of site 2.…”

“…This is clearly the case in transgenic mice, which express G129R-hPRL at concentrations 10 -100-fold higher than endogenous PRL. 2 These mice fail to exhibit any of the phenotypes observed in PRLR knockout mice (40), such as female sterility and mammary gland failure, but instead exhibit certain phenotypes reminiscent of moderate hyperprolactinemia, such as constitutive MAPK activation in the prostate (see below).…”

Transgenic mouse models of human breast cancer

“…Mice lacking the prolactin hormone itself show arrested mammary gland development. Crosses between the prolactin knockouts and mice expressing the viral oncogene polyomavirus middle T antigen (PyV mT) under MMTV control show slower induced tumor growth than in mice expressing PyV mT alone (Wennbo and Tornell, 2000).…”