Constitutive β-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development

Berthon, Annabel; Sahut‐Barnola, Isabelle; Lambert-Langlais, Sarah; Joussineau, Cyrille de; Damon-Soubeyrand, Christelle; Louiset, Estelle; Taketo, M.; Tissier, Frédérique; Bertherat, Jérôme; Lefrançois-Martinez, Anne Marie; Martinez, Antoine; Val, Pierre

doi:10.1093/hmg/ddq029

Cited by 206 publications

(229 citation statements)

References 60 publications

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“…One potential mechanism could be the activation of the WNT/b-catenin pathway. Indeed, it has been shown that this pathway is activated in w70% of APA (Boulkroun et al 2011, Berthon et al 2014), that in rare cases somatic activating mutations of CTNN1B, coding for b-catenin, have been described in APA (Azizan et al 2013, Scholl et al 2013 and that constitutive b-catenin activation in the adrenal cortex induces ectopic ZG differentiation and dedifferentiation of the orthotopic ZF, resulting in hyperaldosteronism in 10-month-old mice (Berthon et al 2010). However some of these mice develop malignant characteristics, such as uncontrolled neovascularization and local invasion, a phenotype rarely observed in patients with PA (Berthon et al 2010); it is possible that the levels of b-catenin dosage play a role in the development of specific types of tumors within the adrenal cortex (Berthon et al 2014).…”

Section: Familial Hyperaldosteronism Type IImentioning

confidence: 99%

An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for w50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.

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Section: Familial Hyperaldosteronism Type IImentioning

confidence: 99%

An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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“…Several lines of evidence suggest that β-catenin plays an important role in adrenal zonation and maintenance. Activation of the β-catenin pathway is restricted to the ZG (Kim et al 2008;Walczak et al 2014), and ectopic expression leads to the activation of ZG markers in ZF cells (Berthon et al 2010). Moreover, β-catenin seems to bind to and control the expression of At1r, a gene specifically expressed within the ZG (Berthon et al 2014).…”

mentioning

confidence: 99%

The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3

Vidal¹,

Sacco²,

Rocha³

et al. 2016

Genes Dev.

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Adrenal glands are zonated endocrine organs that are essential in controlling body homeostasis. How zonation is induced and maintained and how renewal of the adrenal cortex is ensured remain a mystery. Here we show that capsular RSPO3 signals to the underlying steroidogenic compartment to induce β-catenin signaling and imprint glomerulosa cell fate. Deletion of RSPO3 leads to loss of SHH signaling and impaired organ growth. Importantly, Rspo3 function remains essential in adult life to ensure replenishment of lost cells and maintain the properties of the zona glomerulosa. Thus, the adrenal capsule acts as a central signaling center that ensures replacement of damaged cells and is required to maintain zonation throughout life.

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“…These activate Wnt signaling by preventing b-catenin degradation, thereby causing proliferation, but any role in cortisol production remains to be determined (9,10). In mice, constitutive activation of b-catenin causes adrenal hyperplasia, the development of malignant characteristics, and, interestingly, primary aldosteronism in the absence of hypercortisolism (11). Mutations in GNAS, the stimulatory G-protein a-subunit associated with the melanocortin receptor 2, were initially discovered to be the cause of macronodular adrenal hyperplasias (12) and are less frequent causes of cortisol-producing adenomas (6).…”

mentioning

confidence: 99%

PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases

Thiel

Reis

Haase

et al. 2015

European Journal of Endocrinology

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Objective: Cortisol excess due to adrenal adenomas or hyperplasia causes Cushing's syndrome. Recent genetic studies have identified a somatic PRKACA L206R mutation as a cause of cortisol-producing adenomas. We aimed to compare the clinical features of PRKACA-mutant lesions with those of CTNNB1 mutations, and to search for similar mutations in unilateral hyperplasia or tumors co-secreting aldosterone. Design, patients, and methods: In this study, 60 patients with cortisol excess who had adrenalectomies at our institution between 1992 and 2013 were assessed, and somatic mutations were determined by Sanger sequencing. A total of 36 patients had overt Cushing's syndrome, the remainder were subclinical: 59 cases were adenomas (three bilateral) and one was classified as hyperplasia. Four tumors had proven co-secretion of aldosterone.Results: Among cortisol-secreting unilateral lesions without evidence of co-secretion (nZ52), we identified somatic mutations in PRKACA (L206R) in 23.1%, CTNNB1 (S45P, S45F) in 23.1%, GNAS (R201C) in 5.8%, and CTNNB1CGNAS (S45P, R201H) in 1.9%. PRKACA and GNAS mutations were mutually exclusive. Of the co-secreting tumors, two (50%) had mutations in KCNJ5 (G151R and L168R). The hyperplastic gland showed a PRKACA L206R mutation, while patients with bilateral adenomas did not have known somatic mutations. PRKACA-mutant lesions were associated with younger age, overt Cushing's syndrome, and higher cortisol levels vs non-PRKACA-mutant or CTNNB1-mutant lesions. CTNNB1 mutations were more significantly associated with right than left lesions. Conclusions: PRKACA L206R is present not only in adenomas, but also in unilateral hyperplasia and is associated with more severe autonomous cortisol secretion. Bilateral adenomas may be caused by yet-unknown germline mutations.

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Constitutive β-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development

Cited by 206 publications

References 60 publications

An update on novel mechanisms of primary aldosteronism

An update on novel mechanisms of primary aldosteronism

The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3

PRKACA mutations in cortisol-producing adenomas and adrenal hyperplasia: a single-center study of 60 cases

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