The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells

Durán-Prado, Mario; Gahete, Manuel D.; Hergueta-Redondo, Marta; Martínez-Fuentes, Antonio J.; Córdoba-Chacón, José; Palacios, José; Gracia‐Navarro, Francisco; Moreno‐Bueno, Gema; Malagón, Marı́a M.; Luque, Raúl M.; Castaño, Justo P.

doi:10.1038/onc.2011.389

Cited by 69 publications

(102 citation statements)

References 42 publications

(51 reference statements)

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“…Although we observed no differences in the SSTR-induced actions on the tested pathways between the two adenoma subtypes, this does not preclude that SSTR2 and SSTR5 may differentially regulate other intracellular signals that determine the pattern of GH-containing secretory granules. Recently described truncated SSTR5 variants have been described with different signalling behaviour compared with fulllength SSTR5 and further expand the spectrum of possible regulatory interactions (32,33). The SSTR5 antibody used in this study was raised against the C-terminus of SSTR5, which is not present in these truncated SSTR5 variants.…”

Section: Discussionmentioning

confidence: 99%

“…The mouse MABs for SSTR1, 3, 4 and 5 were provided by Novartis, and their specificity has recently been described in detail (31). The SSTR5 antibody was raised against amino acids 350-363 at the very C-terminus of the human SSTR5 (31) and therefore does not recognise recently described truncated SSTR5 variants that arise from alternative splicing at the C-terminus (32,33).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Quantitative RT-PCR analyses for glyceradehyde-3-phosphate-dehydrogenase (GAPDH), the cAMP target gene-inducible cAMP early repressor (ICER), SSTR1 to SSTR5 and ZAC1 were based on previously described primers (27,40,41) and were performed on a Roche Lightcycler 480 using Kapa-SYBR-Fast mixes (PeqLab). The primers for SSTR5 do not detect recently described truncated SSTR5 variants (32,33). Cp values were determined with the second-derivative maximum method (42).…”

Section: Quantitative Rt-pcr and Gsp Genotypingmentioning

confidence: 99%

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Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas

Mayr

Buslei

Theodoropoulou

et al. 2013

European Journal of Endocrinology

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Objective: GH-producing pituitary adenomas display two distinct morphological patterns of cytoplasmic GH-containing secretory granules, namely the densely and sparsely granulated somatotroph adenoma subtype. It is unknown whether these morphological variants reflect distinct pathophysiological entities at the molecular level. Methods: In 28 GH-producing adenoma tissues from a consecutive set of patients undergoing pituitary surgery for acromegaly, we studied the GH granulation pattern, the expression of somatostatin receptor subtypes (SSTR) as well as the calcium, cAMP and ZAC1 pathways in primary adenoma cell cultures.Results: The expression of GSP oncogene was similar between densely and sparsely granulated somatotroph adenoma cells. There were no differences in the calcium, cAMP and ZAC1 pathways as well as in their regulation by SSTR agonists. SSTR2 was exclusively expressed in densely but not in sparsely granulated tumours (membrane expression 86 vs 0%; cytoplasmic expression 67 vs 0%). By contrast, expression of SSTR5 was only found in sparsely but not in densely granulated somatotroph adenomas (membrane expression 29 vs 0%; cytoplasmic expression 57 vs 0%). Conclusions: Our results indicate that different granulation patterns in GH-producing adenomas do not reflect differences in pathways and factors pivotal for somatotroph differentiation and function. In vitro, the vast majority of both densely and sparsely granulated tumour cells were responsive to SSTR activation at the molecular level. Sparsely granulated adenomas lacking SSTR2, but expressing SSTR5, might be responsive to novel SSTR agonists with increased affinity to SSTR5.

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Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Quantitative Rt-pcr and Gsp Genotypingmentioning

confidence: 99%

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Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas

Mayr

Buslei

Theodoropoulou

et al. 2013

European Journal of Endocrinology

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“…Thus, for example, expression of sst5TMD4 in pituitary adenomas causing acromegaly is related to the reduced ability of octreotide at normalizing hormone secretion in poorly responsive tumors in vivo (34). In breast cancer, the presence of sst5TMD4 (which is negligible in the normal mammary gland) is associated with markers of poor prognosis [lower levels of estrogen receptor (ER), HER2/Neu, and p53], and its expression in breast cancer model cell lines was shown to increase malignancy features (cell proliferation, signaling, invasiveness, and migration) by disrupting normal sst2 function (35). Such observations suggest a potential role for these novel truncated receptor variants in tumor diagnosis as a prognostic marker and as therapeutic targets.…”

Section: Somatostatin Receptor Signalingmentioning

confidence: 99%

Molecular Pathogenesis of Neuroendocrine Tumors: Implications for Current and Future Therapeutic Approaches

Öberg

Casanovas

Castaño

et al. 2013

Clinical Cancer Research

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The treatment landscape and biologic understanding of neuroendocrine tumors (NET) has shifted dramatically in recent years. Recent studies have shown that somatostatin analogues have the potential not only to control symptoms of hormone hypersecretion but also have the ability to slow tumor growth in patients with advanced carcinoid. The results of clinical trials have further shown that the VEGF pathway inhibitor sunitinib and the mTOR inhibitor everolimus have efficacy in patients with advanced pancreatic NETs. The efficacy of these targeted therapies in NET suggests that the molecular characterization of NETs may provide an avenue to predict both which patients may benefit most from the treatment and to overcome potential drug resistance. Recent genomic studies of NETs have further suggested that pathways regulating chromatin remodeling and epigenetic modification may play a key role in regulating NET growth. These observations offer the potential for new therapeutic and diagnostic advances for patients with NET.

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“…The interaction of the psst1 with itself or with other pssts was evaluated using the fluorescence resonance energy transfer (FRET) method, as described previously (13)(14)(15). Briefly, images of HEK-293 AD transfected cells were acquired with an inverted Nikon Eclipse TE2000 E scope equipped with a 400 DCLP dichroic filter (Chroma) and recorded with an ORCA II BT digital camera, both controlled with the MetaMorph software (Imaging, West Chester, PA).…”

Section: Protein Extraction and Western Blot Analysismentioning

confidence: 99%

Porcine sst1 can physically interact with other somatostatin receptors, and its expression is regulated by metabolic/inflammatory sensors

Gahete

Durán-Prado

Delgado-Niebla

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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The majority of the biological actions attributed to somatostatin (SST) are thought to be mediated by SST receptor 2 (sst2), the most ubiquitous sst, and, to a lesser extent, by sst5. However, a growing body of evidence suggests a relevant role of sst1 in mediating SST actions in (patho)physiological situations (i.e., endometriosis, type 2 diabetes). Moreover, sst1 together with sst2 and sst5 is involved in the well-known actions of SST on pituitary somatotropes in pig and primates. Here, we cloned the porcine sst1 (psst1) and performed a structural and functional characterization using both primary and heterologous models. The psst1 sequence presents the majority of signature motifs shared among G proteincoupled receptors and, specifically, among ssts and exhibits a high homology with other mammalian sst1, with only minor differences in the amino-terminal domain, reinforcing the idea of an early evolutive divergence between mammalian and nonmammalian sst1s. psst1 is functional in terms of decreasing cAMP levels in response to SST when transfected in heterologous models. The psst1 receptor is expressed in several tissues, and analyses of gene cis elements predict regulation by multiple transcription factors and metabolic stimuli. Finally, psst1 is coexpressed with other sst subtypes in various tissues, and in vitro data demonstrate that psst1 can interact with itself forming homodimers and with other ssts forming heterodimers. These data highlight the functional importance of sst1 on the SST-mediated effects and its functional interaction with different ssts, which point out the necessity of exploring the consequences of such interactions. somatostatin receptor 1, promoter regulation; expression profile; heterodimerization; fluorescence resonance energy transfer; adenosine 3=,5=-cyclic monophosphate SOMATOSTATIN (SST) is a peptide hormone mainly produced by neuroendocrine cells (18,50). It was first isolated from the ovine hypothalamus (6), and soon thereafter isolated and sequenced in porcine hypothalami (45). SST acts as an endogenous inhibitory regulator of various cellular functions, including hormone secretion, motility, and proliferation (5,11,26,32,36,40). SST has two active forms (14 and 28 amino acids) with comparable subnanomolar affinity for a family of G protein-coupled receptors (GPCRs) widely distributed in the brain and periphery and named SST receptors (ssts) (34, 36). To date, five separate sst genes have been described (sst1-sst5), encoding six to nine different isoforms, depending on the species (10,14,16,36). Although more than one sst subtype can be simultaneously expressed in certain cell types, the expression pattern and levels depend on the tissue, the age, and the physiological status (11,29,36).The majority of biological actions associated with SST are thought to be mediated by sst2, the most ubiquitous sst, and, to a lesser extent, by sst5. However, a growing body of evidence suggests a relevant role of sst1 in mediating SST actions in physiological and pathophysiological situations. I...

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The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells

Cited by 69 publications

References 42 publications

Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas

Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas

Molecular Pathogenesis of Neuroendocrine Tumors: Implications for Current and Future Therapeutic Approaches

Porcine sst1 can physically interact with other somatostatin receptors, and its expression is regulated by metabolic/inflammatory sensors

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