Correlation and expression of p53, HER-2, vascular endothelial growth factor (VEGF), and e-cadherin in a high-risk breast-cancer population

Howard, Eugene M.; Lau, Stephen K.; Lyles, Robert H.; Birdsong, George G.; Tadros, Talaat S.; Umbreit, Jay N.; Kochhar, Ruby

doi:10.1007/s10147-004-0386-4

Cited by 21 publications

(19 citation statements)

References 34 publications

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“…Similar to the mouse tumors, concurrent expression of ErbB2 and E-cadherin has been reported for breast cancer, with ErbB2 expression positively correlating with E-cadherin levels (45). These results contradict the commonly held premise that E-cadherin is generally lost in aggressive cancers, suggesting that sustained E-cadherin is a characteristic of ErbB2-induced tumorigenesis, possibly contributing to collective migration of these tumor cells.…”

Section: P120 Mediates Erbb2-induced Migration/invasioncontrasting

confidence: 56%

HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42

Johnson¹,

Seachrist²,

DeLeon-Rodriguez³

et al. 2010

Journal of Biological Chemistry

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Breast cancers that overexpress the receptor tyrosine kinase ErbB2/HER2/Neu result in poor patient outcome because of extensive metastatic progression. Herein, we delineate a molecular mechanism that may govern this malignant phenotype. ErbB2 induction of migration requires activation of the small GTPases Rac1 and Cdc42. The ability of ErbB2 to activate these small GTPases necessitated expression of p120 catenin, which is itself up-regulated by signaling through ErbB2 and the tyrosine kinase Src. Silencing p120 in ErbB2-dependent breast cancer cell lines dramatically inhibited migration and invasion as well as activation of Rac1 and Cdc42. In contrast, overexpression of constitutively active mutants of these GTPases reversed the effects of p120 silencing. Lastly, ectopic expression of p120 promoted migration and invasion and potentiated metastatic progression of a weakly metastatic, ErbB2-dependent breast cancer cell line. These results suggest that p120 acts as an obligate intermediate between ErbB2 and Rac1/Cdc42 to modulate the metastatic potential of breast cancer cells.HER2/Neu/ErbB2 (epidermal growth factor receptor 2) is a member of the epidermal growth factor receptor (EGFR) 2 family that is amplified and overexpressed in 20 -30% of breast cancers. HER2/ErbB2-positive breast cancer yields a poor patient prognosis because of a high incidence of metastases and intrinsic resistance to endocrine and conventional chemotherapy (1). ErbB2 is the preferred heterodimerization partner for EGFR, ErbB3, and ErbB4 (2). The large range of downstream signaling targets induced by ErbB2-containing heterodimers permits this receptor and its partners to modulate a wide array of cellular processes. Of these, the nonreceptor tyrosine kinase Src, PI3K, and MAPK pathways are the most studied in mediating ErbB2 responsiveness, which includes increased proliferation, survival, motility, and invasion (3).ErbB2-induced cell migration and invasion, and hence metastatic potential, requires activation of Src and its downstream signaling pathways (4). Src also positively provides feedback and stabilizes competent ErbB2/ErbB3 heterocomplexes to enhance PI3K/Akt signaling (5). ErbB2 overexpression in MDA-MB-435 cells enhances formation of metastases by increasing Src synthesis and decreasing its degradation by calpain (6). Similarly, signaling from ErbB2 to Akt is necessary to promote metastatic potential because attenuation of the Akt pathway by pharmacological inhibitors or RNAi decreases the formation of metastases by the ErbB2-dependent 21T breast cancer cell line (7).

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Section: P120 Mediates Erbb2-induced Migration/invasioncontrasting

confidence: 56%

HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42

Johnson¹,

Seachrist²,

DeLeon-Rodriguez³

et al. 2010

Journal of Biological Chemistry

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“…Patterns of E-cadherin protein expression in infiltrating ductal carcinoma (IDC) clinical specimens also suggest a role for E-cadherin in the progression of IDC. Unlike infiltrating lobular carcinomas which consistently display a loss of E-cadherin expression regardless of clinical staging or outcome [10][11][12], over 80% of IDCs continue to express E-cadherin, albeit at a progressively reduced level, with increasing stage or histological grade [13][14][15]. A similar trend is noted among cases of ductal carcinoma in situ where level of E-cadherin expression positively correlates with degree of differentiation [16].…”

Section: Introductionmentioning

confidence: 49%

E-cadherin Immunohistochemical Expression as a Prognostic Factor in Infiltrating Ductal Carcinoma of the Breast: a Systematic Review and Meta-Analysis

Rothberg

Bracken

2006

Breast Cancer Res Treat

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Loss of E-cadherin expression may be an independent negative prognostic indicator for infiltrating ductal breast carcinoma and randomized, controlled studies evaluating this finding are justified. We encourage standardization of immunohistochemical techniques, data interpretation algorithms across laboratories and use of all-cause mortality to increase data compatibility and facilitate future efforts summarizing the utility of alternate prognostic markers in cancer.

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“…Presence of regulatory mechanisms that down-regulate the immune response to TAA in the periphery has been recognized in rHER-2 transgenic mice and human patients (46,47). These mechanisms include negative T regulatory cells (2), immature myeloid cells (48), regulation of endothelial adhesiveness (49), and creation of an anti-inflammatory environment at the tumor site (50). Here we show that central tolerance contributes to impairment of immune responsiveness in BALB-neuT mice through a quantitative reduction of the T cell repertoire available.…”

Section: Discussionmentioning

confidence: 99%

Distinct and Non-Overlapping T Cell Receptor Repertoires Expanded by DNA Vaccination in Wild-Type and HER-2 Transgenic BALB/c Mice

Rolla

Nicolò

Malinarich

et al. 2006

The Journal of Immunology

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Central tolerance to tumor-associated Ags is an immune-escape mechanism that significantly limits the TCR repertoires available for tumor eradication. The repertoires expanded in wild-type BALB/c and rat-HER-2/neu (rHER-2) transgenic BALB-neuT mice following DNA immunization against rHER-2 were compared by spectratyping the variable (V)β and the joining (J)β CDR 3. Following immunization, BALB/c mice raised a strong response. Every mouse used one or more CD8+ T cell rearrangements of the Vβ9-Jβ1.2 segments characterized by distinct length of the CDR3 and specific for 63-71 or 1206-1214 rHER-2 peptides. In addition, two CD4+ T cell rearrangements recurred in >50% of mice. Instead, BALB-neuT mice displayed a limited response to rHER-2. Their repertoire is smaller and uses different rearrangements confined to CD4+ T cells. Thus, central tolerance in BALB-neuT mice acts by silencing the BALB/c mice self-reactive repertoire and reducing the size of the CD8+ T cell component. CD8+ and CD4+ T cells from both wild-type and transgenic mice home to tumors. This definition of the T cell repertoires available is critical to the designing of immunological maneuvers able to elicit an effective immune reaction against HER-2-driven carcinogenesis.

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Correlation and expression of p53, HER-2, vascular endothelial growth factor (VEGF), and e-cadherin in a high-risk breast-cancer population

Cited by 21 publications

References 34 publications

HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42

HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42

E-cadherin Immunohistochemical Expression as a Prognostic Factor in Infiltrating Ductal Carcinoma of the Breast: a Systematic Review and Meta-Analysis

Distinct and Non-Overlapping T Cell Receptor Repertoires Expanded by DNA Vaccination in Wild-Type and HER-2 Transgenic BALB/c Mice

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