EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis

Ettl, Tobias; Stiegler, Clemens; Zeitler, Katharina; Agaimy, Abbas; Zenk, Johannes; Reichert, Torsten E.; Gosau, Martin; Kühnel, Thomas; Brockhoff, Gero; Schwarz, Stephan

doi:10.1016/j.humpath.2011.08.006

Cited by 62 publications

(55 citation statements)

References 49 publications

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“…6E). Importantly, our findings may explain the accumulating controversies regarding the tumor suppressor function of STAT3 in various cancer types (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). For instance, there are many publications in which the immune-detection of pSTAT3 Y705 or nuclear STAT3 was found to significantly correlate with a better outcome (9)(10)(11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 65%

“…The oncogenic potential of STAT3 has been well documented; specifically, the constitutively activated STAT3 mutant (commonly labeled STAT3C) can effectively induce malignant transformation (4), and many human cancers harbor constitutively active STAT3 (1)(2)(3). Nevertheless, accumulating evidence from both experimental and clinical studies has suggested that STAT3 may also carry a tumor suppressor role in specific contexts (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). For instance, in a mouse model of intestine adenoma, tissue-specific STAT3 gene knockout was found to enhance tumor invasion and promote tumor progression (5,6).…”

Section: Introductionmentioning

confidence: 99%

“…STAT3 expression was found to be reduced in the majority of skin squamous cell carcinomas compared with adjacent nonmalignant tissues (8). Moreover, nuclear-STAT3 or pSTAT3 Y705 was shown to correlate with a better prognosis in multiple cancers, such as head and neck squamous cell carcinoma, salivary gland cancer, low-grade or node-negative breast cancer, colorectal cancer, and nasopharyngeal carcinoma (9)(10)(11)(12)(13)(14). In a recent review article, we have speculated that the molecular basis of how STAT3 can function as a tumor suppressor and oncoprotein may be related to the existence of two STAT3 isoforms, STAT3a and STAT3b (3).…”

Section: Introductionmentioning

confidence: 99%

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The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

Zhang

Chen

et al. 2016

Clinical Cancer Research

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Purpose: STAT3 is known to have both oncogenic and tumor suppressive effects, but the regulation of these opposing effects is elusive. We hypothesized that STAT3b, one of the two STAT3 isoforms, is the key determinant in this context.Experimental Design: The prognostic significance of STAT3b and phospho-STAT3a Y705 (pSTAT3a Y705 ) was evaluated in 286 cases of patients with esophageal squamous cell carcinoma (ESCC). STAT3b-induced changes in the chemosensitivity to cisplatin and 5-fluorouracil were assessed both in vitro and in vivo. STAT3b-induced changes in the frequency of cancer stem cells were evaluated using Hoechst and CD44 staining. How STAT3b regulates STAT3a was determined using immunoprecipitation, confocal microscopy, DNA-binding, and chromatin immunoprecipitation-PCR.Results: STAT3b expression is an independent protective prognostic marker in patients with ESCC, which strongly correlated with longer overall survival (P ¼ 0.0009) and recurrence-free survival (P ¼ 0.0001). STAT3b significantly decreased the cancer stem cell population, and sensitized ESCC cells to cisplatin and 5-fluorouracil in tumor xenografts. Mechanistically, STAT3b markedly attenuated the transcription activity of STAT3a via inducing STAT3a:STAT3b heterodimers. However, the heterodimer formation decreased the binding between STAT3a and PTPN9 (better known as PTP-MEG2), a protein tyrosine phosphatase, thereby promoting the phosphorylation of STAT3a Y705 and enhancing its nuclear translocation and DNA binding. Correlating with this, high STAT3b expression converts the prognostic value of pSTAT3a Y705 from unfavorable to favorable in patients with ESCC.Conclusions: STAT3b suppresses chemoresistance and cancer stemness by blocking the transcriptional activity of STAT3a. The paradoxical increase in pSTAT3a Y705 induced by STAT3b carries important implications as to how the biologic and prognostic significance of STAT3 in cancers should be interpreted. Clin Cancer Res; 22(3); 691-703. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

Zhang

Chen

et al. 2016

Clinical Cancer Research

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“…Fan et al reported EGFR expression in ~92% of SDC cases (17), and a marginally significant correlation of EGFR overexpression in SDC with local recurrence was observed (19). Furthermore, EGFR overexpression in salivary gland tumors was found to be correlated with poor prognosis and appeared to play an important role in tumorigenesis (38,39). Although anti-EGFR targeted therapies are expected to provide novel treatment options, no previous reports have detailed their effectiveness for SDC.…”

Section: Sdc Was First Described In 1968 Bymentioning

confidence: 99%

Salivary duct carcinoma treated with cetuximab-based targeted therapy: A case report

Kawahara

Hiraki

Yoshida

et al. 2017

Molecular and Clinical Oncology

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Abstract. Salivary duct carcinoma is a highly aggressive disease with a poor prognosis. Surgical resection is currently the only curative treatment, as there is no effective systemic therapy for this malignancy. Recently, trastuzumab has been shown to exhibit therapeutic efficacy in the treatment of salivary duct carcinoma; similarly, molecularly targeted agents, such as cetuximab, are expected to be useful for salivary duct carcinoma treatment. We herein describe the case of a 56-year-old man diagnosed with salivary duct carcinoma in the left submandibular region, with ipsilateral multiple metastases to the neck lymph nodes. Radical resection of the tumor and submandibular gland with neck dissection were performed. One month after radical surgery, computed tomography (CT) scans indicated metastasis in the lower lobe of the left lung. CT-guided transthoracic fine-needle aspiration biopsy revealed a single metastasis and lung metastasectomy was immediately performed. The tumor cells of the primary lesion and those of the lung metastasis were immunohistochemically positive for epidermal growth factor receptor. One month later, multiple right lung metastases appeared, and the patient was treated with cisplatin/5-fluorouracil (5-FU) chemotherapy plus cetuximab, achieving a complete radiographic response. However, multiple lung metastases developed during adjuvant weekly cetuximab monotherapy. Subsequently, treatment with S-1 and weekly cetuximab was initiated, and the multiple lung metastases have been maintained as stable disease for 5 months. To the best of our knowledge, this is the first report of cetuximab use for the treatment of salivary duct carcinoma. Although cisplatin/5-FU chemotherapy plus cetuximab was efficacious in treating the lung metastasis, cetuximab monotherapy was insufficient for controlling tumor growth.

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“…In human breast cancer, gene amplification and protein overexpression of ERBB-2 are associated with poor prognosis (10). Similarly, highgrade human salivary gland carcinomas harbor increased ERBB-2 protein expression and gene copy number (11).…”

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confidence: 99%

Multiple Roles of Perforin in Hampering ERBB-2 (Her-2/neu) Carcinogenesis in Transgenic Male Mice

Macagno

Bandini

Stramucci

et al. 2014

The Journal of Immunology

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Perforin (pfp)-mediated cytotoxicity is one of the principal immunosurveillance mechanisms involved in the fight against cancer. However, its importance in spontaneous epithelial cancer is still poorly defined. In this study, we use a realistic mouse model that displays many features that are equivalent to human pathology to evaluate the role of pfp-dependent immunosurveillance by comparing tumor progression in rat ERBB-2 (neu) transgenic, pfp-proficient (neu+/pfp+) or pfp-deficient (neu+/pfp−) BALB/c male mice. Adult neu+/pfp+ males developed poorly differentiated salivary carcinomas, whereas neu+/pfp− males displayed their salivary carcinomas noticeably earlier and showed zones of more highly differentiated tumor, indicating that pfp-mediated immunosurveillance is able not only to delay the growth kinetic of an aggressive epithelial tumor, but also to shape its histology. The role of pfp-mediated immunosurveillance appeared to be of even more dramatic importance against the less aggressive male mammary carcinomas. In neu+/pfp+ males, the incidence of mammary carcinomas was a sporadic and late event. In contrast, in neu+/pfp− males their incidence was four-fold higher. This higher cancer incidence was associated with a 2-fold higher occurrence of persisting mammary remnants, a major risk factor for mammary cancer in male mice, and one that would appear to be due to pfp’s previously unidentified involvement in male mammary gland rejection during embryogenesis. This work thus provides further proof of the complex role that the immune system plays in the body and gives new insight into the pathogenesis of epithelial tumors, demonstrating that the penetrance and malignancy of a tumor may be dramatically affected by pfp-dependent mechanisms.

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EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis

Cited by 62 publications

References 49 publications

The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

Salivary duct carcinoma treated with cetuximab-based targeted therapy: A case report

Multiple Roles of Perforin in Hampering ERBB-2 (Her-2/neu) Carcinogenesis in Transgenic Male Mice

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