Expression of EGFR, VEGF, and NOTCH1 Suggest Differences in Tumor Angiogenesis in HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma

Troy, Jesse D.; Weissfeld, Joel L.; Youk, Ada O.; Thomas, Sufi M.; Wang, Lin; Grandis, Jennifer R.

doi:10.1007/s12105-013-0447-y

Cited by 40 publications

(28 citation statements)

References 41 publications

(69 reference statements)

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“…RPPA analyses revealed that HPV(+) OPSCC expressed lower levels of EGFR (Figure 1A and Table 2) and, although not significant, had decreased expression of activated EGFR (EGFR pY1173, p = 0.05, and EGFR pY992, p = 0.07, Supplemental Table 1). These data support described inverse correlation between HPV-positivity and EGFR expression (20). Downstream targets of EGFR activity were also expressed at relatively lower levels in HPV(+) compared to HPV(−) tumors, including STAT3 and activated MEK1/2 (phospho-S217).…”

Section: Resultssupporting

confidence: 89%

Reverse-Phase Protein Array Profiling of Oropharyngeal Cancer and Significance of PIK3CA Mutations in HPV-Associated Head and Neck Cancer

Sewell

Brown

Biktasova

et al. 2014

Clinical Cancer Research

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Purpose HPV-associated (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) have different molecular and biological characteristics and clinical behavior compared to HPV-negative (HPV−) OPSCC. PIK3CA mutations are more common in HPV(+)OPSCC. To define molecular differences and tumor subsets, protein expression and phosphorylation were compared between HPV(+) and HPV(−) OPSCC and between tumors with and without PIK3CA mutations. Experimental design Expression of 137 total and phosphorylated proteins was evaluated by reverse phase protein array(RPPA) in 29 HPV(+) and 13 HPV(−)prospectively collected OPSCCs. 47 OPSCCs were tested for hotspot activating mutations in PIK3CA and AKT. Activation of PIK3CA downstream targets and sensitivity to pathway inhibitors were determined in HPV(+) head and neck cancer cells overexpressing wild-type or mutant PIK3CA. Results Analyses revealed forty-one differentially expressed proteins between HPV(+) and HPV(−) OPSCC categorized into functional groups: DNA repair, cell cycle, apoptosis, PI3K/AKT/mTOR, and receptor kinase pathways. All queried DNA repair proteins were significantly upregulated in HPV(+) samples. 8 of 33 HPV(+) and 0 of 14 HPV(−) tumors contained activating PIK3CA mutations. Despite all activating PIK3CA mutations occurring in HPV(+) samples, HPV(+) tumors had lower mean levels of activated AKT and downstream AKT target phosphorylation. Ectopic expression of mutant PIK3CA in HPV(+) cells increase dmTOR, but not AKT activity. HPV E6/E7 overexpression inhibited AKT phosphorylation in HPV-negative cells. Mutant PIK3CA overexpressing cells were more sensitive to a dual PI3K/mTOR inhibitor compared to an AKT inhibitor. Conclusions Protein expression analyses suggest that HPV(+) and HPV(−) OPSCC differentially activate DNA repair, cell cycle, apoptosis, PI3K/AKT/mTOR, and receptor kinase pathways. PIK3CA mutations are more common in HPV(+) OPSCC and are associated with activation of mTOR, but not AKT. These data suggest that inhibitors for mTOR may have activity against HPV(+) PIK3CA mutant oropharyngeal cancers.

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Section: Resultssupporting

confidence: 89%

Reverse-Phase Protein Array Profiling of Oropharyngeal Cancer and Significance of PIK3CA Mutations in HPV-Associated Head and Neck Cancer

Sewell

Brown

Biktasova

et al. 2014

Clinical Cancer Research

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“…The association between EGFR overexpression and HPV-negative, but not HPV-positive, HNSCC has been reported previously 32-35 . Our data also showed similar results (data not shown).…”

Section: Discussionmentioning

confidence: 61%

Human papillomavirus 16 oncoprotein regulates the translocation of β‐catenin via the activation of epidermal growth factor receptor

Müller

Qian

et al. 2014

Cancer

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BACKGROUND:To understand the mechanism of frequent and early lymph node metastasis in high-risk human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC), this study investigated whether b-catenin is regulated by the HPV oncoprotein and contributes to OPSCC metastasis. METHODS: Expression levels of p16, b-catenin, and epidermal growth factor receptor (EGFR) were examined in OPSCC samples (n 5 208) by immunohistochemistry. The expression and subcellular localization of b-catenin and EGFR activation were also studied in HPV-positive and HPV-negative head and neck squamous cell carcinoma cell lines with western blot analysis. HPV16 E6 small interfering RNA was used to elucidate the effect of the HPV oncoprotein on bcatenin translocation. The involvement of EGFR in b-catenin translocation was confirmed by treatment with erlotinib. Moreover, the invasive capacity was evaluated after HPV16 E6/E7 repression. RESULTS: The results showed that the membrane weighted index of b-catenin was inversely correlated with p16 positivity (P <.001) and lymph node metastasis (P 5.026), whereas nuclear staining of bcatenin was associated with p16-positive OPSCC (P <.001). A low level of membrane b-catenin expression was significantly associated with disease-free and overall survival (P <.0001 in both cases). Furthermore, the membrane weighted index of EGFR was inversely correlated with p16 positivity (P <.001) and positively correlated with membrane b-catenin (P <.001). The in vitro study showed that HPV16 E6 repression led to reductions of phospho-EGFR and nuclear b-catenin, which were also observed after erlotinib treatment, and inhibition of invasion. CONCLUSIONS: The findings suggest that HPV16 E6 mediates the translocation of b-catenin to the nucleus, which may be regulated by activated EGFR. Cancer 2015;121:214-25.

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“…The impact of HPV status on response to cetuximab therapy is incompletely understood. Others reported that endogenous expression of the HPV oncogenes in vitro did not significantly impact response to EGFR inhibition, and response rates to cetuximab in patients with HPV[+] and HPV[−] HNSCC were similar (9). However, cetuximab is rarely administered in the clinic as a monotherapy (26), thus evaluating the direct relationship between HPV status and response to cetuximab therapy has been challenging.…”

Section: Discussionmentioning

confidence: 99%

“…HPV oncogenes have not been shown to modulate the anti-EGFR antibody responses in HNSCC (6, 8). Others have found that EGFR is selectively overexpressed in HPV[−] HNSCC (9). HER2 and HER3 have been associated with other HPV-associated cancers (10, 11).…”

Section: Introductionmentioning

confidence: 99%

Increased Expression of HER2, HER3, and HER2:HER3 Heterodimers in HPV-Positive HNSCC Using a Novel Proximity-Based Assay: Implications for Targeted Therapies

Pollock

Wang

Wallweber³

et al. 2015

Clinical Cancer Research

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Purpose In other cancer types, HPV infection has been reported to coincide with overexpression of HER2 and HER3, however the association between HER2 or HER3 expression or dimer formation in HNSCC has not been reported. Overexpression of HER2 and HER3 may contribute to resistance to EGFR inhibitors, including cetuximab, although the contribution of HPV in modulating cetuximab response remains unknown. Determination of heterodimerization of HER receptors is challenging and has not been reported in HNSCC. The present study aimed to determine the expression of HER proteins in HPV[+] versus HPV[−] HNSCC tumors using a proximity-based protein expression assay (VeraTag), and to determine the efficacy of HER targeting agents in HPV[+] and HPV[−] HNSCC cell lines. Experimental Design Expression of total HER1, HER2, and HER3, p95HER2, p-HER3, HER1:HER1 homodimers, HER2:HER3 heterodimers and the HER3-PI3K complex in 88 HNSCC was determined using VeraTag, including 33 baseline tumors from individuals treated in a trial including cetuximab. Inhibition of cell growth and protein activation with cetuximab and afatinib was compared in HPV[+] and HPV[−] cetuximab-resistant cell lines. Results Expression of total HER2, total HER3, HER2:HER3 heterodimers, and the HER3:PI3K complex were significantly elevated in HPV[+] HNSCC. Total EGFR was significantly increased in HPV[−] HNSCC where VeraTag assay results correlated with IHC. Afatinib significantly inhibited cell growth when compared to cetuximab in the HPV[+] and HPV[−] cetuximab-resistant HNSCC cell lines. Conclusion These findings suggest that agents targeting multiple HER proteins may be effective in the setting of HPV[+] HNSCC and/or cetuximab resistance.

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Expression of EGFR, VEGF, and NOTCH1 Suggest Differences in Tumor Angiogenesis in HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma

Cited by 40 publications

References 41 publications

Reverse-Phase Protein Array Profiling of Oropharyngeal Cancer and Significance of PIK3CA Mutations in HPV-Associated Head and Neck Cancer

Reverse-Phase Protein Array Profiling of Oropharyngeal Cancer and Significance of PIK3CA Mutations in HPV-Associated Head and Neck Cancer

Human papillomavirus 16 oncoprotein regulates the translocation of β‐catenin via the activation of epidermal growth factor receptor

Increased Expression of HER2, HER3, and HER2:HER3 Heterodimers in HPV-Positive HNSCC Using a Novel Proximity-Based Assay: Implications for Targeted Therapies

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