Low Level Her2 Overexpression Is Associated with Rapid Tumor Cell Proliferation and Poor Prognosis in Prostate Cancer

Minner, Sarah; Jessen, Birte; Stiedenroth, Lars; Burandt, Eike; Köllermann, Jens; Mirlacher, Martina; Erbersdobler, Andreas; Eichelberg, Christian; Fisch, Margit; Brümmendorf, Tim H.; Bokemeyer, Carsten; Simon, Ronald; Steuber, Thomas; Graefen, Markus; Huland, Hartwig; Sauter, Guido; Schlomm, Thorsten

doi:10.1158/1078-0432.ccr-09-2546

Cited by 127 publications

(130 citation statements)

References 45 publications

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“…For instance, in prostate cancer HER2 overexpression is rarely observed, and these tumors typically exhibit low surface HER2 levels. 24 Thus, antibody-mediated clearance mechanisms such as phagocytosis and ADCC may be significantly abrogated in such tumors. This may also contribute to the disappointing results observed in clinical trials with anti-HER2 antibody treatments in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

The level of HER2 expression is a predictor of antibody-HER2 trafficking behavior in cancer cells

Ram

Kim

Ober

et al. 2014

mAbs

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The receptor tyrosine kinase HER2 is known to play a central role in mitogenic signaling, motivating the development of targeted, HER2-specific therapies. However, despite the longstanding use of antibodies to target HER2, controversies remain concerning antibody/HER2 trafficking behavior in cancer cells. Understanding this behavior has direct relevance to the mechanism of action and effective design of such antibodies. In the current study, we analyzed the intracellular dynamics of trastuzumab, a marketed HER2-targeting antibody, in a panel of breast and prostate cancer cell lines that have a wide range of HER2 expression levels. Our results reveal distinct post-endocytic trafficking behavior of antibody-HER2 complexes in cells with different HER2 expression levels. In particular, HER2-overexpressing cells exhibit efficient HER2 recycling and limited reductions in HER2 levels upon antibody treatment, and consequently display a high level of antibody persistence on their plasma membrane. By contrast, in cells with low HER2 expression, trastuzumab treatment results in rapid antibody clearance from the plasma membrane combined with substantial decreases in HER2 levels and undetectable levels of recycling. A cell line with intermediate levels of HER2 expression exhibits both antibody recycling and clearance from the cell surface. Significantly, these analyses demonstrate that HER2 expression levels, rather than cell origin (breast or prostate), is a determinant of subcellular trafficking properties. Such studies have relevance to optimizing the design of antibodies to target HER2.

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Section: Discussionmentioning

confidence: 99%

The level of HER2 expression is a predictor of antibody-HER2 trafficking behavior in cancer cells

Ram

Kim

Ober

et al. 2014

mAbs

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“…18 The tissue microarray manufacturing process was described earlier in detail. 19,20 In short, one 0.6 mm core was taken from a representative tissue block from each patient. The tissues were distributed among 10 tissue microarray blocks, each containing 129-522 cores.…”

Section: Patientsmentioning

confidence: 99%

Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions

et al. 2013

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6q12-22 is the second most commonly deleted genomic region in prostate cancer. Mapping studies have described a minimally deleted area at 6q15, containing MAP3K7/TAK1, which was recently shown to have tumor suppressive properties. To determine prevalence and clinical significance of MAP3K7 alterations in prostate cancer, a tissue microarray containing 4699 prostate cancer samples was analyzed by fluorescence in situ hybridization. Heterozygous MAP3K7 deletions were found in 18.48% of 2289 interpretable prostate cancers. MAP3K7 deletions were significantly associated with advanced tumor stage (Po0.0001), high Gleason grade (Po0.0001), lymph node metastasis (Po0.0108) and early biochemical recurrence (Po0.0001). MAP3K7 alterations were typically limited to the loss of one allele as homozygous deletions were virtually absent and sequencing analyses revealed no evidence for MAP3K7 mutations in 15 deleted and in 14 non-deleted cancers. There was a striking inverse association of MAP3K7 deletions and TMPRSS2:ERG fusion status with 26.7% 6q deletions in 1125 ERG-negative and 11.1% 6q deletions in 1198 ERG-positive cancers (Po0.0001). However, the strong prognostic role of 6q deletions was retained in both ERG-positive and ERG-negative cancers (Po0.0001 each). In summary, our study identifies MAP3K7 deletion as a prominent feature in ERG-negative prostate cancer with strong association to tumor aggressiveness. MAP3K7 alterations are typically limited to one allele of the gene. Together with the demonstrated tumor suppressive function in cell line experiments and lacking evidence for inactivation through hypermethylation, these results indicate MAP3K7 as a gene for which haploinsufficency is substantially tumorigenic. Modern Pathology (2013) 26, 975-983; doi:10.1038/modpathol.2012 published online 1 February 2013 Keywords: ERG; MAP3K7; prostate cancerIn prostate cancer a variety of chromosomal deletions occur frequently, whereas gains of chromosomal material and high-level amplification occur rarely in this tumor. 1,2 Deletions of 6q12-22 have been described to occur in 22-62% of prostate cancers. 1-5 6q12-22 deletions rank second in the

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“…Presence or absence of cancer tissue was validated by immunohistochemical AMACR and 34BE12 analysis. 16 The molecular database attached to this TMA contained results on ERG expression in 9,628, ERG break apart FISH analysis in 6 21 and 3p13 deletions and breakage (FOXP1) in 1,814 tumors. 22 …”

Section: Patientsmentioning

confidence: 99%

Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer

Kluth

Harasimowicz

Burkhardt

et al. 2014

Intl Journal of Cancer

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Despite a multitude of p53 immunohistochemistry (IHC) studies, data on the combined effect of nuclear p53 protein accumulation and TP53 genomic inactivation are lacking for prostate cancer. A tissue microarray including 11,152 prostate cancer samples was analyzed by p53 IHC and fluorescence in situ hybridization. Nuclear p53 accumulation was found in 10.1% of patients including 1.4% with high-level and 8.7% with low-level immunostaining. TP53 sequencing revealed that 17 of 22 (77%) cases with high-level p53 immunostaining, but only 3% (1 of 31) low-level p53 cases carried putative dominantnegative mutations. TP53 deletions occurred in 14.8% of cancers. Both deletions and protein accumulation were linked to unfavorable tumor phenotype and prostate specific antigen (PSA) recurrence (p < 0.0001 each). The combination of both methods revealed subgroups with remarkable differences in their clinical course. Tumors with either TP53 deletion (14%) or lowlevel p53 positivity (8.7%) had identical risks of PSA recurrence, which were markedly higher than in cancers without p53 alterations (p < 0.0001). Tumors with both p53 deletion and low-level p53 positivity (1.5%) had a worse prognosis than patients with only one of these alterations (p < 0.0001). Tumors with strong p53 immunostaining or homozygous inactivation through deletion of one allele and disrupting translocation involving the second allele had the worst outcome, independent from clinical and pathological parameters. These data demonstrate a differential clinical impact of various TP53 alterations in prostate cancer. Strong p53 immunostaining-most likely accompanying dominant negative or oncogenic p53 mutation-has independent prognostic relevance and may thus represent a clinical useful molecular feature of prostate cancer.Dysregulation of the p53 tumor suppressor belongs to the most frequent genetic alterations in malignant tumors. Reduced p53 function compromises cellular programs inducing apoptosis in DNA damaged cells and consequently enables tumor progression through acquisition of additional genetic changes. Mechanisms for TP53 inactivation include functionally relevant point mutations of the gene as well as gross chromosomal alterations, mostly 17p deletions. Disrupting breaks of the TP53 gene have only recently been described as an alternative mechanism for p53 inactivation. 1 Furthermore, at least certain p53 mutations can exhibit oncogenic properties through mutation-specific protein interactions that may be independent of the physiological gene function. For example, transgenic mice with particular p53 mutations develop a spectrum of primary cancers and metastases that is more aggressive and phenotypically different from those observed in mice with a p53-null allele. 2 Irrespective of their functional consequences, tumorigenic p53 mutations frequently accompany markedly increased levels of altered p53 protein in affected cells. 3 Immunohistochemistry (IHC) is thus commonly used to detect p53-mutated cancers.In prostate cancer, p53 alterations are less c...

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Low Level Her2 Overexpression Is Associated with Rapid Tumor Cell Proliferation and Poor Prognosis in Prostate Cancer

Cited by 127 publications

References 45 publications

The level of HER2 expression is a predictor of antibody-HER2 trafficking behavior in cancer cells

The level of HER2 expression is a predictor of antibody-HER2 trafficking behavior in cancer cells

Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions

Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer

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