P. Touraine

Prolactin and Human Tumourogenesis

The involvement of prolactin in human tumourogenesis has been long debated. The reason is that the evidence supporting the role of circulating prolactin in promoting breast cancer was mainly obtained using rodent models, whereas most of the studies performed in human species in the 1980s have remained inconclusive. Things have now started to change because two alternative mechanisms of prolactin actions in tumour growth have emerged since the beginning of the 21st Century. The first involves locally‐produced prolactin, which acts by an autocrine/paracrine mechanism. Genetically‐modified mouse models have demonstrated the tumourigenic potential of local prolactin on the prostate and the mammary gland, and arguments are now emerging in humans also. The second mechanism involves genetic variants of the receptor. Although no genetic disorder has been reported for prolactin or its receptor, a variant of the prolactin receptor exhibiting constitutive activity has been recently identified in patients presenting with breast tumours, suggesting that sustained prolactin signalling may participate in breast tumourogenesis. Recent data regarding these two nonclassical mechanisms of prolactin action are discussed. Finally, we address the question of their inhibition in future cancer therapy, both in light of other findings that have revealed novel actions of prolactin in breast cancer cells, and with respect to the compounds currently available to target prolactin receptor signalling.

Drug Insight: prolactin-receptor antagonists, a novel approach to treatment of unresolved systemic and local hyperprolactinemia?

Prolactin is a polypeptide hormone whose major biological actions are related to normal lactation and reproduction. Abnormally high prolactin levels, referred to as hyperprolactinemia, can result in various reproductive disorders. Currently, therapeutic management of hyperprolactinemia relies on dopamine agonists, since dopamine is the primary physiological suppressor of pituitary prolactin production. Epidemiologic studies have shown that prolactin levels in the high-normal range, as well as medications that interfere with dopamine action (e.g. certain antipsychotic drugs), might correlate with increased breast cancer risk. In addition to circulating prolactin, it is now well established that prolactin is also produced locally within various tissues, including breast and prostate. Increasing evidence, mainly from animal studies at present, suggests that excess locally produced prolactin may promote the growth of breast and prostate tumors via an autocrine or paracrine mechanism. These findings have renewed the interest in finding alternative strategies to suppress prolactin actions when dopamine agonists are ineffective. Our studies of the relationship between prolactin structure and function have resulted in the development of pure prolactin-receptor antagonists. These molecules prevent endogenous prolactin from exerting its actions via a competitive mechanism for receptor binding. In this review, we discuss the possible future therapeutic utility of this novel class of compounds.

Identification of Gain-of-Function Variants of the Human Prolactin Receptor

There is currently no known genetic disease linked to prolactin (PRL) or its receptor (PRLR) in humans. Recently, we identified three missense variants of the PRLR in patients presenting with breast tumors. Two of them (named PRLR(I146L) and PRLR(I76V)) had been reported earlier, but failed to draw much attention because the eventual impact of these substitutions on receptor properties remained unknown. In this chapter, we describe the various bioassays (cell types and readouts) that led to the discovery that both variants exhibit gain-of-function properties. Reconstituted cell models involving Ba/F3, HEK293, and MCF-7 cell lines all highlighted the constitutive, PRL-independent potency of PRLR(I146L) to trigger downstream signaling, leading to antiapoptotic and proliferation properties. The lower level of basal activity of PRLR(I76V) could be demonstrated only in the very sensitive Ba/F3 cell assay. While comparative analysis of ligands is a routine procedure in many labs, comparison of receptor variants de facto imposes the use of different cell clones (or population) in which each receptor variant is expressed individually. This is more delicate, as one must ensure that differences in biological responses really reflect differences in the intrinsic properties of receptor variants, and not any feature of cell clones/populations that are used, which could bias the interpretation.

Monocentric study of 112 consecutive patients with childhood onset GH deficiency around and after transition

OBJECTIVES Our aim was to analyze a large cohort of childhood onset GH deficiency (CO-GHD) adults from a unique adult center, in order to analyze their clinical management and to study the metabolic and bone status in relation to GHD and to the other pituitary deficits, and to evaluate these parameters during the long-term follow-up. DESIGN AND METHODS Observational retrospective cohort study on 112 consecutive CO-GHD adults transferred to our unit from 1st January 1994 to 1st March 2012. Evaluation of GHD in pediatrics and after transition was conducted following consensus guidelines. Data recorded from pediatric and adult files were GH doses, pituitary magnetic resonance imaging and function, and metabolic and bone status. RESULTS Most patients presented with severe CO-GHD (64%) associated with other pituitary deficits (66%). CO-GHD was acquired in 56%, congenital in 33%, and idiopathic in 11% cases. Most patients (83%) stopped GH before transfer, at 16.3 years (median), despite persistence of GHD. Median age at transfer was 19.4 years. After transfer, GHD persisted in 101 patients and four of the 11 resolutive GHD were non idiopathic. IGF1 level was <-2 SDS in 70% of treated patients at transfer and in 34% of them after 3 years of treatment. Follow-up showed improvement in lipid profile and bone mineral density in severely persistent GHD patients under GH therapy. In multivariate analysis, the associated pituitary deficits seemed stronger determinant factors of metabolic and bone status than GHD. CONCLUSIONS This study raises concern about discontinuation of GH replacement therapy in pediatrics in severely persistent GHD patients and about the often insufficient dose of GH in the treatment of adult patients.

Autocrine prolactin as a promotor of mammary tumour growth

Prolactin (PRL) plays a key role in normal growth, development and differentiation of the mammary gland. Indeed, strong evidence suggests that the development of alveolar cells requires not only oestradiol and progesterone, but also PRL. In vitro , PRL has mitogenic activity on normal mouse mammary epithelial cells (reviewed in Das & Vonderhaar, 1997). In vivo , PRL also seems to be involved in such proliferative activity, although it is more difficult to distinguish the role of PRL from the influence of the hormonal milieu (Das & Vonderhaar, 1997). This physiological role of PRL in lobular development of the mammary gland is supported by results obtained from mice deficient for PRL (Horseman et al. 1997) or for its receptor (PRLR) (Ormandy et al. 1997). Although the infertility of females homozygous for the deletion of the PRLR gene (PRLR −/− ) can be partially reversed by restoring progesterone levels close to normal, their mammary gland fails to differentiate during pregnancy, leading to lactation failure (Binart et al. 2000). In addition, heterozygous mice (PRLR +/− ), who have half normal receptor levels, show impaired mammary gland development and fail to lactate following their first pregnancy, clearly indicating that signals mediated by the PRL/PRLR interaction have to achieve a certain level to permit mammary gland differentiation and lactation (Kelly et al. 2002). Since the pioneering work of Topper (Topper, 1970), who observed that PRL was necessary to induce casein synthesis, our understanding of the mechanism of such induction has greatly expanded. PRL appears to be the primary hormone involved in this activity, although other hormones such as insulin and glucocorticoids are also required for lactation.

Suivi prospectif de 60 femmes présentant une polyadénomatose mammaire : description radiologique et facteurs influant sur son évolution

Introduction: La polyadenomatose mammaire (PAM) etant une maladie benigne rare du sein, son histoire naturelle est mal connue. Le but de notre travail etait donc de decrire radiologiquement le devenir d’une cohorte de patientes presentant une PAM, et d’evaluer l’influence de differents facteurs sur son evolution. Methodes: Il s’agit d’une etude prospective de cohorte. Les patientes incluses ont beneficie de deux evaluations clinico-biologiques et radiologiques (echographie et IRM mammaires) a au moins 5 ans d’intervalle. Resultats: Soixante femmes ont ete suivies sur 7,4±1,7 ans en moyenne. L’evolution radiologique a montre une diminution du nombre de fibroadenomes (FA) dans 55% des cas a l’echographie et 36,6% a l’IRM ; associee a une diminution de taille dans 93% des cas. Une augmentation du nombre de FA etait retrouvee dans environ 40% des cas, avec, pour la majorite, a une diminution de la taille des lesions (69,6% a l’echographie et 87% a l’IRM). Le tabac (p=0,04) et l’IMC (p=0,01) etaient associees a une aggravation de la PAM, alors que la grossesse (p=0,001) ainsi que l’allaitement (p=0,001) ou encore la prise de traitement hormonal (p=0,01) en particulier le lynestrenol (p<0,0001) etaient associes a une amelioration de la PAM. Ces trois derniers avaient egalement un effet benefique sur l’evolution de la PAM entre les deux evaluations. Des antecedents senologiques familiaux etaient retrouves dans plus de 40% des cas, et les antecedents familiaux de cancer du sein etaient aussi associes une amelioration de la PAM (p=0,06). Une incidence de 3,3% de cancers et de 8% de tumeurs phyllodes a ete observee dans notre population. Conclusion: Il s’agit de la premiere etude longitudinale de femmes presentant une PAM. L’evolution radiologique de cette pathologie semble favorable et similaire a celle attendue d’un FA simple. Nous avons identifie des facteurs influencant l’evolution de la PAM, et notamment les macroprogestatifs type lynestrenol qui pourraient avoir un effet benefique. Poursuivre le suivi de notre cohorte permettrait d’approfondir davantage nos connaissances sur cette pathologie, notamment concernant le risque de cancer du sein.