Quantification of insulin receptor mRNA splice variants as a diagnostic tumor marker in breast cancer

Aljada, Ahmad; Saleh, Ayman M.; Alaqeel, Suliaman; Shamsa, Heba Bani; Al-Bawab, Ahmad; Dubayee, Mohammed Al; Ahmed, Altayeb Abdalla

doi:10.3233/cbm-150505

Cited by 22 publications

(19 citation statements)

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“…No correlations were found between IR levels and age, body weight, menopausal status, and nodal involvement of breast cancer patients [10]. Aljada et al showed that mRNA levels of IR were significantly higher in cancer patients presented with advanced clinical stage of the disease compared to early stages [44]. As our findings demonstrate, a favorable prognostic impact for IR expression in breast cancer tissues and IR expression may be perceived as a marker of differentiation [43].…”

Section: Discussionsupporting

confidence: 43%

Expression of Insulin Receptor and c-MET Is Associated with Clinicopathologic Characteristics and Molecular Subtypes in Premenopausal Breast Cancer Patients

et al. 2020

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Receptor Tyrosine Kinases (RTKs) represent a class of transmembrane receptors known to play an important role in cancer development and progression. In this study, the expression of insulin receptor (IR) and the hepatocyte growth factor receptor (c-MET) was examined in breast cancer patients. Immunohistochemistry for IR and c-MET was performed on 71 cases of invasive breast cancer and expression scores were correlated with clinicopathologic characteristics and molecular subtypes and further stratified based on a menopausal status. Expression of IR was significantly associated with the tumor grade (p = 0.017) and estrogen receptor (ER) expression (p = 0.015). There was a significant positive correlation between IR and c-MET expression scores (rho = 0.458, p < 0.001). Among premenopausal cases, IR scores were significantly higher in patients with grade I/II disease (p = 0.025), ER-positive (p = 0.030), and progesterone receptor (PR)-positive carcinoma (p = 0.015). c-MET expression scores were significantly higher among premenopausal patients with ER-positive (p = 0.007) and PR-positive carcinoma (p = 0.024). IR expression scores were significantly different among molecular subtypes for all patients (p = 0.006) and among premenopausal cases (p = 0.035). c-MET expression was statistically different among molecular subtypes for premenopausal patients (p = 0.019). Survival analysis revealed that the expression status of IR and c-MET was not associated with overall survival. Our findings support a favorable prognostic value for IR and c-MET expression in premenopausal breast cancer patients.

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Section: Discussionsupporting

confidence: 43%

Expression of Insulin Receptor and c-MET Is Associated with Clinicopathologic Characteristics and Molecular Subtypes in Premenopausal Breast Cancer Patients

et al. 2020

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“…Moreover, IR-A content in HR ER+ cancers was higher than IGF-1R content. In addition, an increased IR-A mRNA expression with a decreased IR-B expression results in an increased IR-A:IR-B ratio, as was detected in human breast cancer ( Table 1 ) [ 30 , 31 ]. The IR isoforms expression is different in distinct breast cancer ER+ subtypes that have a different response to hormone treatment and a different prognosis.…”

Section: Deregulation Of Ir In Cancermentioning

confidence: 91%

Insulin Receptor Isoforms in Cancer

Vella

Milluzzo

Scalisi

et al. 2018

IJMS

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The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.

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“…The second and most important finding, herein described, is the characterization of GL56 anti-IR aptamer. As recently emerged, IR, in addition to regulate important aspects of cellular physiology, 35 , 36 , 37 is overexpressed and overactivated in several cancers 19 , 20 and interfering with its expression (by shRNA) results in the inhibition of tumor growth and metastasis. 13 These data, together with the involvement of the receptor in drug resistance, 21 , 22 strongly indicate that therapeutic strategies directed against the receptor may represent an important challenge in oncology.…”

Section: Discussionmentioning

confidence: 99%

“…Deregulated expression of the IR in its embryonic isoform A and overactivation of the receptor have been demonstrated in several kinds of cancer. 19 , 20 In addition, it has been reported that IR may have an important role in the resistance to various anticancer therapies 21 , 22 and to anti-IGF-1 receptor drugs, 23 strongly indicating the potential of IR targeting. 24 So far, available drugs, generated to inhibit IGF-1R, have generally no inhibiting activity on IR and anticancer strategies specifically targeting the IR are still lacking, thus representing an important challenge in oncology.…”

Section: Introductionmentioning

confidence: 99%

Targeting Insulin Receptor with a Novel Internalizing Aptamer

Iaboni

Fontanella²,

Rienzo

et al. 2016

Molecular Therapy - Nucleic Acids

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Nucleic acid-based aptamers are emerging as therapeutic antagonists of disease-associated proteins such as receptor tyrosine kinases. They are selected by an in vitro combinatorial chemistry approach, named Systematic Evolution of Ligands by Exponential enrichment (SELEX), and thanks to their small size and unique chemical characteristics, they possess several advantages over antibodies as diagnostics and therapeutics. In addition, aptamers that rapidly internalize into target cells hold as well great potential for their in vivo use as delivery tools of secondary therapeutic agents. Here, we describe a nuclease resistant RNA aptamer, named GL56, which specifically recognizes the insulin receptor (IR). Isolated by a cell-based SELEX method that allows enrichment for internalizing aptamers, GL56 rapidly internalizes into target cells and is able to discriminate IR from the highly homologous insulin-like growth factor receptor 1. Notably, when applied to IR expressing cancer cells, the aptamer inhibits IR dependent signaling. Given the growing interest in the insulin receptor as target for cancer treatment, GL56 reveals a novel molecule with great translational potential as inhibitor and delivery tool for IR-dependent cancers.

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Quantification of insulin receptor mRNA splice variants as a diagnostic tumor marker in breast cancer

Abstract: The results demonstrate an increased IR-A:IR-B ratio in all clinical stages of breast cancer. Thus, IR-A:IR-B ratio may have a diagnostic biomarker utility in breast cancer.

Cited by 22 publications

References 0 publications

Expression of Insulin Receptor and c-MET Is Associated with Clinicopathologic Characteristics and Molecular Subtypes in Premenopausal Breast Cancer Patients

Expression of Insulin Receptor and c-MET Is Associated with Clinicopathologic Characteristics and Molecular Subtypes in Premenopausal Breast Cancer Patients

Insulin Receptor Isoforms in Cancer

Targeting Insulin Receptor with a Novel Internalizing Aptamer

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