Prognostic Significance of Overexpression and Phosphorylation of Epidermal Growth Factor Receptor (EGFR) and the Presence of Truncated EGFRvIII in Locoregionally Advanced Breast Cancer

Nieto, Yago; Nawaz, Fatima; Jones, Roy B.; Shpall, Elizabeth J.; Nawaz, Samia

doi:10.1200/jco.2006.09.8822

Cited by 84 publications

(64 citation statements)

References 61 publications

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“…(16) Whether Rab5A played any role in these is not clear; there are few data available on the expression of Rab5A in human breast cancer or its impact on disease progression.…”

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confidence: 99%

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Rab5A is associated with axillary lymph node metastasis in breast cancer patients

Yang

Yin

Tseng³

et al. 2011

Cancer Science

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The expression of Rab proteins has been associated with cancer. However, few data are available on Rab5A expression in human breast cancer or its impact on disease progression. First, we examined the functional role of Rab5A in breast cancer cells. The expression of Rab5A in MDA-MB-231 cells can be stimulated by epidermal growth factor in a dose-dependent manner. The epidermal growth factor-induced increase of Rab5A expression correlated well with enhanced migration in wound healing migration assays in these cells. Furthermore, we evaluated the expression of Rab5A in breast cancer specimens using immunohistochemical staining, then analyzed the relationship between the expression of Rab5A and clinicopathological parameters. The increased expression of Rab5A protein in 123 breast cancer samples was associated with higher histological grade (P = 0.004), more lymphovascular invasion (P = 0.027), more axillary lymph node (LN) metastasis (P = 0.008), and a higher number of axillary LN metastases (P = 0.043). Among 218 axillary LNs of more than 10 breast cancer patients with node metastases, 167 metastatic LNs were found to have increased Rab5A expression. Rab5A is associated with axillary LN metastasis in breast cancer patients. (Cancer Sci 2011; 102: 2172-2178 T he majority of deaths from breast cancer are attributed to metastasis. Axillary LNs are often the first sites of metastasis in breast cancer patients.(1) The presence of axillary LN metastasis is a major criterion in the prognosis and in the decision-making for additional chemotherapy after primary tumor surgeries.(2) Only 20% of systemic metastases derived from tumor cells bypass the lymphatic route.(3) Therefore, axillary LN metastasis is one of the most important issues in breast cancer.Rab GTPases, which are members of the Ras superfamily of small GTPases, are key regulators of membrane trafficking in both exocytic and endocytic pathways as well as receptor localization in eukaryotic cells. (4,5) Many studies have revealed the association between Rab GTPase dysfunction and human diseases, including cancer.(6) Rab5 is one of the most extensively studied members of Rab GTPases.(7) It plays important roles in a variety of cellular trafficking and signaling events, including receptor internalization, targeting and fusion of endocytic vesicles with early endosomes, fusion between early endosomes, actin remodeling, and signaling to the nucleus.(8) Recent studies have revealed that the overexpression of Rab5A is associated with the metastatic potential of lung and gastric cancer, (9,10) is involved in the migration of hepatocellular carcinomas, (11) and promotes ovary cancer cell proliferation.(12) Rab5A mediates the formation of EGFR-containing endosomes. (13,14) The EGFR signaling cascades can promote cell proliferation, angiogenesis, and invasion, and inhibit apoptosis, resulting in tumor growth and progression.(15) Poor prognosis was confirmed in patients of locally advanced breast cancer with overexpression of EGFR. (16) Whether Rab5A played any role in th...

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“…(16) Whether Rab5A played any role in these is not clear; there are few data available on the expression of Rab5A in human breast cancer or its impact on disease progression.…”

mentioning

confidence: 99%

“…(15) Poor prognosis was confirmed in patients of locally advanced breast cancer with overexpression of EGFR. (16) Whether Rab5A played any role in these is not clear; there are few data available on the expression of Rab5A in human breast cancer or its impact on disease progression.…”

mentioning

confidence: 99%

Rab5A is associated with axillary lymph node metastasis in breast cancer patients

Yang

Yin

Tseng³

et al. 2011

Cancer Science

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“…Regardless, some patients also experience intrinsic and acquired resistance, eventually leading to disease progression (2). Several mechanisms of trastuzumab resistance have been elucidated, such as intrinsic alteration in HER2-like truncated HER2 receptors (34), heterodimer formation between other receptor tyrosine kinases (RTKs) and HER2 (35)(36)(37), and constitutive activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway or loss of phosphatase and tensin homolog function (38). Studies have suggested that dual HER2 blockade with trastuzumab and pertuzumab may be significantly associated with clinical outcomes (39,40).…”

Section: Discussionmentioning

confidence: 99%

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells

Zeng

Che

Liu

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the expression of FEN1, and FEN1 knockdown significantly enhanced the sensitivity of BT474 cells to trastuzumab (P<0.05). It was also revealed that trastuzumab induced HER receptor activation, increased binding with FEN1 and estrogen receptor α (ERα), and upregulated ERα-target gene transcription (P<0.05). Upon silencing of FEN1 expression with siRNA, activation of HER receptor and FEN1 binding to ERα were decreased, and trastuzumab-induced ERα target gene upregulation was partially ameliorated (P<0.05). These results suggest that FEN1 may mediate trastuzumab resistance via inducing HER receptor activation and enhancing ERα-target gene transcription. The findings of the present study indicate a novel role of FEN1 in trastuzumab resistance, suggesting that targeting FEN1 may enhance the efficiency of trastuzumab as a treatment for HER2-positive breast cancer.

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“…Overexpression of EGFR is one of clinical features of breast cancer correlating with poor prognosis (36)(37)(38)(39)(40). Many types of molecular targeting drugs against EGFR have been developed for various cancer types including breast cancer (41)(42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis

Ajiro

Nishidate²,

Katagiri³

et al. 2010

Int J Oncol

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Abstract. We previously reported an important role of RQCD1 in mammary carcinogenesis through the interaction with Grb10 interacting GYF protein 1 (GIGYF1), Grb10 interacting GYF protein 2 (GIGYF2) and growth factor receptor binding protein 10 (Grb10). In this study, we investigated the biological mechanism of RQCD1 in regulation of the Akt activity as the downstream signal of epidermal growth factor receptor (EGFR). Knockdown of RQCD1 reduced the Akt phosphorylation level that was induced by epidermal growth factor (EGF) stimulation. We found a possible formation of the big complex involved in the Akt activity including Akt, EGFR, GIGYF1 and GIGYF2, Grb10 and RQCD1. We subsequently defined that a region corresponding to 620-665th amino acids of GIGYF1 and 667-712th amino acids of GIGYF2 interacted with RQCD1. Furthermore, we found that RQCD1 was required for enhancement of the interaction of Grb10 with GIGYF1 and GIGYF2. Our findings in this study imply the functional mechanism of RQCD1 in the Akt activity regulation as a mediator in the EGFR-signaling pathway.

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Prognostic Significance of Overexpression and Phosphorylation of Epidermal Growth Factor Receptor (EGFR) and the Presence of Truncated EGFRvIII in Locoregionally Advanced Breast Cancer

Cited by 84 publications

References 61 publications

Rab5A is associated with axillary lymph node metastasis in breast cancer patients

Rab5A is associated with axillary lymph node metastasis in breast cancer patients

FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells

Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis

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