KAI1/CD82 is a novel target of estrogen receptor‐mediated gene repression and downregulated in primary human breast cancer

Christgen, Matthias; Bruchhardt, Henriette; Ballmaier, Matthias; Krech, Till; Länger, Florian; Kreipe, Hans; Lehmann, Ulrich

doi:10.1002/ijc.23806

Cited by 33 publications

(56 citation statements)

References 33 publications

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“…Increasing attention has been paid to the interaction between different factors involved in metastatic processes in hormone-sensitive tumors [22][23][24]. To our knowledge, this is the first study which has analyzed the association between steroid receptors, KAI1 protein, MMP-2, and MMP-9 -as well as between KAI1, MMP-2, and MMP-9 Table 3.…”

Section: Discussionmentioning

confidence: 99%

“…Correlations between examined biomarkers in endometrial cancers www.fhc.viamedica.pl -in endometrial cancer. Earlier studies revealed that KAI1 protein may cooperate with MMPs, and displays a different role in its functions in ER-negative and ER-positive breast cancers [14,22,23]. Christgen et al [22,23] found that in ER-positive breast cancers the KAI1 protein was downregulated.…”

Section: Discussionmentioning

confidence: 99%

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The relationships between the immunoexpression of KAI1, MMP-2, MMP-9 and steroid receptors expression in endometrial cancer

Gryboś

Bär

2014

Folia Histochem Cytobiol.

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Abstract:The role of the parallel expression of the KAI1 protein and metalloproteinases (MMP-2 and MMP-9) in respect to the status of steroid receptors in endometrial cancer is still incompletely understood. The aim of this study was to evaluate the expression of and correlation between KAI1 on one hand and MMP-2 and MMP-9 on the other hand in terms of the status of the estrogen (ER) and progesterone receptors (PR) in 100 patients with endometrial cancer. The expressions of KAI1, MMP-2, MMP-9, ER and PR were assessed immunohistochemically on paraffin-embedded tissues. No correlations were found between these biomarkers and the clinical and pathological parameters of the endometrial cancer. However, in KAI1-positive cases, the expression was limited to a small area of tumor tissue in FIGO stages III-IV. A tendency towards the high expression of MMP-9 and MMP-2 was observed in the advanced stages of endometrial cancer (FIGO IIIA-IV). Positive correlations between the presence of KAI1 and PR and between the presence of MMP-9 and PR were found in endometrial cancer. A positive correlation was also observed between KAI1 and MMP-2 expression, and a borderline one between KAI1 and MMP-9 expression in endometrial cancer. KAI1 -/MMP-2 + and KAI1 -/MMP-9 + phenotypes were more often observed in FIGO stage II. Our study showed that KAI1 protein, as well as steroid receptors, might modulate MMP-2 and MMP-9 expression in endometrial cancer. Our study revealed that the overlapping expression of the biomarkers investigated here suggests that cooperation between these molecules exists, even at the early stages of endometrial cancer growth, and may determine the speed of tumor cell dissemination and might characterize the biological behavior of endometrial cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The relationships between the immunoexpression of KAI1, MMP-2, MMP-9 and steroid receptors expression in endometrial cancer

Gryboś

Bär

2014

Folia Histochem Cytobiol.

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“…All specimens were made anonymous for scientific purposes and were compiled on tissue microarrays for immunohistochemical assessment of nuclear p53 accumulation as described previously. 41 Clinicopathological characteristics are reported in Supplementary Table 1.…”

Section: Tumor Specimensmentioning

confidence: 99%

IPH-926 lobular breast cancer cells harbor a p53 mutant with temperature-sensitive functional activity and allow for profiling of p53-responsive genes

Christgen

Noskowicz

Heil

et al. 2012

Laboratory Investigation

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Profiling of p53-responsive genes has been carried out in different cellular models, most of which involved genetic modifications or cytotoxic stimulation. We report on the utilization of IPH-926 human lobular breast cancer cells for the profiling of p53-responsive genes using a novel approach without such modifications. We discovered that IPH-926 cells harbor a homozygous TP53 missense mutation encoding for a rare p53 mutant (E285K) with temperature-sensitive (ts) loss of function characteristics. This mutation had evolved as a late, secondary genetic event during the natural clonal evolution of the corresponding lobular carcinoma. In vitro temperature shifts reconstituted endogenous wild-type p53 activity in IPH-926, as evidenced by induction of p21Waf1 . Transcriptional alterations associated with restored p53 function were profiled using Affymetrix microarrays and a new strategy to gate out non-specific temperature effects. At the P ¼ 0.0005 significance level, 60 genes were differentially expressed following reconstitution of p53 activity. These genes included CDKN1A, MDM2 and PHLDA3, a recently described p53-inducible inhibitor of AKT. Similar transcriptional alterations were observed upon reconstitution of p53 activity in BT-474 cells, which also harbor ts-p53 E285K, and in ASPC1 cells transduced with ts-p53 A138V. Consistent with these models, low PHLDA3 expression was associated with nuclear p53 accumulation, indicative of deleterious TP53 mutations, in primary breast cancers. From a molecular point of view, IPH-926 thus provides a new tool to study transcriptional programs controlled by p53. From a tumor pathology perspective, IPH-926 also provides the first direct evidence of a p53-related clonal evolutionary pathway in lobular breast cancer progression. Mutational inactivation of the TP53 tumor suppressor gene encoding for p53 is frequent in human breast cancer, especially in estrogen receptor (ER)-negative, medullary, basallike and BRCA1-related cases. 1-4 The p53 protein functions as a stress-induced transcription factor that regulates various cellular processes, such as growth arrest, apoptosis and energy metabolism. 5 External stresses that stabilize p53, and thus induce p53 signaling, include DNA-damaging agents and hypoxia. 6 Internal stresses that induce p53 signaling include activation of oncogenes, such as PIK3CA and PTEN. 7 Characterization of p53 transcriptional targets is of importance for understanding how mutational inactivation of TP53 promotes tumor initiation and progression. Profiling of p53-responsive genes has been carried out in different cellular models. Some of these models relied on cytotoxic cell stimulation for induction of a p53 response. 8,9 Other models utilized genetically engineered cells, which overexpressed wild-type (wt) p53, TP53 targeting shRNAs for p53 knockdown, or p53 inactivating polypeptides for functional neutralization of p53. [10][11][12][13][14][15][16] Another useful approach has been ectopic overexpression of the murine, temperature-sensitive (ts) p53 mi...

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“…1 However, it is not appropriate to dismiss our approaches, methods, and findings as a ''replication of portions of a paper'' published by Huang et al 2 In addition, several results of our study are not cited correctly by Dr. Geradts:…”

Section: Dear Sirmentioning

confidence: 85%

Reply to: Letter to the editor from Dr. Geradts

Christgen

2009

Intl Journal of Cancer

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Dear Sir,We appreciate the comment of Dr. Geradts on our recent work concerning the expression and regulation of KAI1/CD82 in human breast cancer. 1 However, it is not appropriate to dismiss our approaches, methods, and findings as a ''replication of portions of a paper'' published by Huang et al. 2 In addition, several results of our study are not cited correctly by Dr. Geradts:i. The study of Huang et al. sought to validate several of about 300 candidate genes proposed to be differentially expressed in Her2-positive vs. Her2-negative breast cancer and focused primarily on Net-6. The expression of Net-6 was confirmed to correlate with a positive Her2 status in primary breast cancers. Subsequently, MDA-MB-231 cells were transfected with a Net-6 expression vector and subjected to in vitro assays demonstrating the invasion and growth inhibitory function of Net-6. In the text of this publication, it was stated that reduced immunoreactivity for another candidate gene, KAI1, was not associated with Her2-immunoreactivity but occurred significantly more frequently in estrogen receptor (ER)-positive cases. We really apologize for not having noticed and cited this piece of information given in the text, but not the abstract of a publication focussing on Her2-signalling in breast cancer and therefore not directly related to our study. ii. Our own work concerning KAI1 evolved independently from a totally different starting point: Stark et al. have recently reported the downregulation of KAI1 mRNA in a small number of brain metastases from human breast cancer. 3 Therefore, we were interested to analyse KAI1 mRNA and protein expression in a large set of formalinfixed paraffin-embedded brain metastases from human breast cancer, which we have described earlier. 4 For this purpose, we developed a staining protocol for the compa ratively new anti-KAI1 antibody from Santa Cruz (clone G2, Santa Cruz, Santa Cruz, CA) and established a suitable positive control with a very high KAI1 mRNA and protein expression level (UACC-893). In contrast to Huang et al., we presented a detailed analysis of KAI1 immunoreactivity and KAI1 mRNA expression in a large set of well-characterized human primary breast cancers. Also, in vitro experiments disclosing a role of ER activity in the regulation of KAI1 expression as well as the results of data-mining approaches using published expression data sets were provided. The manuscript describing the expression of KAI1 in our panel of distant organ metastases (primarily brain and liver) from breast cancer is currently in preparation. iii. We acknowledge that Huang et al. 2 employed the same anti-KAI1-antibody. However, contrary to the statements of Dr.

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KAI1/CD82 is a novel target of estrogen receptor‐mediated gene repression and downregulated in primary human breast cancer

Cited by 33 publications

References 33 publications

The relationships between the immunoexpression of KAI1, MMP-2, MMP-9 and steroid receptors expression in endometrial cancer

The relationships between the immunoexpression of KAI1, MMP-2, MMP-9 and steroid receptors expression in endometrial cancer

IPH-926 lobular breast cancer cells harbor a p53 mutant with temperature-sensitive functional activity and allow for profiling of p53-responsive genes

Reply to: Letter to the editor from Dr. Geradts

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