Identification and Characterization of Two Novel Truncated but Functional Isoforms of the Somatostatin Receptor Subtype 5 Differentially Present in Pituitary Tumors

Durán-Prado, Mario; Gahete, Manuel D.; Martínez-Fuentes, Antonio J.; Luque, Raúl M.; Quintero, A.; Webb, Susan M.; Benito-López, Pedro; Leal, Alfonso; Schulz, Stefan; Gracia‐Navarro, Francisco; Malagón, Marı́a M.; Castaño, Justo P.

doi:10.1210/jc.2008-2564

Cited by 123 publications

(142 citation statements)

References 33 publications

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“…Splice variants of the human SSTR5 gene have been found in pituitary adenomas (Duran-Prado et al 2009), but the encoded truncated isoforms cannot be detected by the anti-SSTR5 antibody we used, which is directed against the C-terminal region of the receptor. SSTR1 expression was investigated in 40 adenomas of the test cohort, including the recurrences, and in 10 tumors of the validation cohort.…”

Section: Discussionmentioning

confidence: 99%

SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary

Lee¹,

Lupp²,

Mendoza³

et al. 2014

Endocrine-Related Cancer

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Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not amenable to complete surgical resection. Radiotherapy is the only post-operative option for patients with large invasive or recurrent lesions. No medical treatment is available for these patients. The somatostatin analogs (SSAs) octreotide and lanreotide that preferentially target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted that the expression of specific SSTR subtypes determines the response to SSAs. Given that previous studies on mRNA and protein expression of SSTRs in GPAs have generated conflicting results, we investigated the expression of SSTR2, SSTR3, and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well-characterized cohort of 108 patients with GPAs. A total of 118 samples were examined by immunohistochemistry using validated and specific MABs. Matched primary and recurrent tissues were available for ten patients. The results obtained were validated in an independent cohort of 27 GPAs. We observed that SSTR3 was significantly more abundant than SSTR2 (P!0.0001) in GPAs, while full-length SSTR5 was only expressed in few tumors. Expression of SSTR3 was similar in primary and recurrent adenomas, was high in potentially aggressive lesions, and did not change significantly in adenomas that recurred after irradiation. In conclusion, low levels of expression of SSTR2 may account for the limited response of GPAs to octreotide and lanreotide. Given the potent anti-proliferative, pro-apoptotic, and anti-angiogenic activities of SSTR3, targeting this receptor with a multireceptor ligand SSA such as pasireotide may be indicated for potentially aggressive GPAs.

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Section: Discussionmentioning

confidence: 99%

SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary

Lee¹,

Lupp²,

Mendoza³

et al. 2014

Endocrine-Related Cancer

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“…The specific rabbit-antiserum against sst5TMD4 has been previously described and characterized (Duran-Prado et al, 2009). Goat-anti-SST2 and goat-anti-SST5 were purchased from Santa Cruz (Santa Cruz, CA, USA).…”

Section: Antiseramentioning

confidence: 99%

“…Additionally, we recently identified two new truncated sst5 variants, sst5TMD5 and sst5TMD4, generated by non-canonical splicing, which are overexpressed in pituitary tumors (Duran-Prado et al, 2009), where they have a negative role, hindering the normal response of tumor cells to SST analogs (Dura´n-Prado et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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Somatostatin receptors (sst1-5) are present in different types of tumors, where they inhibit key cellular processes such as proliferation and invasion. Although ssts are densely expressed in breast cancer, especially sst2, their role and therapeutic potential remain uncertain. Recently, we identified a new truncated sst5 variant, sst5TMD4, which is related to the abnormal response of certain pituitary tumors to treatment with somatostatin analogs. Here, we investigated the possible role of sst5TMD4 in breast cancer. This study revealed that sst5TMD4 is absent in normal mammary gland, but is abundant in a subset of poorly differentiated human breast tumors, where its expression correlated to that of sst2. Moreover, in the MCF-7 breast cancer model cell, sst5TMD4 expression increased malignancy features such as invasion and proliferation abilities (both in cell cultures and nude mice). This was likely mediated by sst5TMD4-induced increase in phosphorylated extracellular signal-regulated kinases 1 and 2 and p-Akt levels, and cyclin D3 and Arp2/3 complex expression, which also led to mesenchymal-like phenotype. Interestingly, sst5TMD4 interacts physically with sst2 and thereby alters its signaling, enabling disruption of sst2 inhibitory feedback and providing a plausible basis for our findings. These results suggest that sst5TMD4 could be involved in the pathophysiology of certain types of breast tumors.

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“…Such biomarkers include the acute octreotide test, the presence of a gsp mutation, the expression of E-cadherin, the expression of sst5 and its truncated isoform (sst5TMD4), the expression of miR-34a, the expression of β-arrestin, the Ki-67 labeling index and the Raf kinase expression 57,68,72,83,[86][87][88][89][90][91] . Additionally, some demographic characteristics, such as younger age, male gender and high pretreatment GH levels were associated with a poor response to fg-SRL in some studies [92][93][94] .…”

Section: Biomarkers Of Treatment Response In Acromegalymentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Personalized medicine in the treatment of acromegaly

Kasuki

Wildemberg

2018

European Journal of Endocrinology

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Acromegaly is associated with high morbidity and elevated mortality when not adequately treated. Surgery is the first-line treatment for most patients as it is the only one that can lead to immediate cure. In patients who are not cured by surgery, treatment is currently based on a trial-and-error approach. Firstgeneration somatostatin receptor ligands (fg-SRL) are initiated for most patients, although approximately 25% of patients present resistance to this drug class. Some biomarkers of treatment outcome are described in the literature, with the aim of categorizing patients into different groups to individualize their treatments using a personalized approach. In this review, we will discuss the current status of precision medicine for the treatment of acromegaly and future perspectives on the use of personalized medicine for this purpose.

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Identification and Characterization of Two Novel Truncated but Functional Isoforms of the Somatostatin Receptor Subtype 5 Differentially Present in Pituitary Tumors

Cited by 123 publications

References 33 publications

SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary

SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary

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

MANAGEMENT OF ENDOCRINE DISEASE: Personalized medicine in the treatment of acromegaly

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