RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis
<p>NF-κB (nuclear factor kappaB) activity in inflammatory breast cancer (IBC) cell lines. Equal concentrations of total protein from nuclear or cytoplasmic extracts were loaded into a gel and immunoblotted (IB) with the phospho-NF-κB p65 antibody that recognizes the p65 subunit phosphorylated at S536. PCNA (Proliferating cell nuclear antigen) expression is used as a control for nuclear fraction, and Actin is used as a control for cytoplasmic fraction. Signal was developed using enhanced chemiluminescence (ECL). Data shown are representative of the results of at least three independent experiments.</p> "> Figure 2
<p>RIPK2 is hyperactive in IBC cell lines: (<b>a</b>) equal concentrations of samples were loaded and immunoblotted (IB) with an antibody to the active form of RIPK2 using a RIPK2 phospho (p) –Serine (S) 176, RIPK2 phospho (p) -tyrosine (Y) 474 or an antibody that recognizes total RIPK2. GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) expression is used as a loading control for whole cell lysate. Signal was developed using enhanced chemiluminescence (ECL). * <span class="html-italic">p</span>-value for the difference between MCF 10A and KPL4, SUM149, and MDA-IBC-3 is 0.01, 0.02, and 0.004, respectively. ** <span class="html-italic">p</span>-value for the difference between MCF7 and KPL4, SUM149, and MDA-IBC-3 are 0.02, 0.03, and 0.001; (<b>b</b>) luminescent ADP-Glo in vitro RIPK2 kinase assay in breast cancer cell lines. RIPK2 was immunoprecipitated and kinase activity was then measured by quantifying luminescence (RLU) that correlates to the percentage of ADP produced during the enzymatic reaction as per manufacture instructions. * <span class="html-italic">p</span>-value for the difference between MCF 10A and KPL4, SUM149, and MDA-IBC-3 are 0.004, 0.09, and 0.04, respectively. ** <span class="html-italic">p</span>-value for the difference between MCF7 and KPL4, SUM149, and MDA-IBC-3 is 0.01, 0.03, and 0.02, respectively; and (<b>c</b>) radioactive in vitro kinase assay in different breast cancer cell lines (cut from the same gel). RIPK2 was immunoprecipitated and kinase activity was then determined using radioactively labeled ATP. The autophosphorylation site of Y474 of RIPK2 is visualized using standard autoradiography. All the data shown are representative of the results of two to four independent experiments. KPL4 revealed similar constitutively active level of RIPK2 [<a href="#B43-cancers-10-00184" class="html-bibr">43</a>].</p> "> Figure 3
<p>Immunohistochemical staining of normal non-neoplastic breast: (<b>a</b>) luminal A; (<b>b</b>) luminal B; (<b>c</b>) <span class="html-italic">HER2</span> overexpressed; (<b>d</b>) triple negative breast cancer (TNBC); (<b>e</b>) and IBC; (<b>f</b>) using RIPK2 phospho-Y474 antibody). Breast tissue was stained and visualized using horseradish peroxidase-conjugated secondary antibody and 3, 3′ diaminobenzidine (DAB; brown), red scale bar: 50 µm, black scale bar: 20 µm. DAB staining of luminal A (<span class="html-italic">n</span> = 7), luminal B (<span class="html-italic">n</span> = 8), <span class="html-italic">HER2</span> overexpressed (<span class="html-italic">n</span> = 7), TNBC (<span class="html-italic">n</span> = 10) and IBC (<span class="html-italic">n</span> = 18). Tissue was quantified using the ImageJ platform permitting integrated optical density assessment of regions of interested in each slide. ImageJ analyzed images were then normalized to normal breast tissue (<span class="html-italic">n</span> = 17) imaged in a similar manner; and (<b>g</b>) the plot represents the fold change in RIPK2 phospho-Y474 expression in tumor tissue relative to normal non-neoplastic breast tissues. <span class="html-italic">p</span>-value is calculated against normal breast tissue. All breast cancer tissues were isolated from patients after neoadjuvant chemotherapy treatment. A description of our patient population is documented in <a href="#cancers-10-00184-t001" class="html-table">Table 1</a> (in the Materials and Methods <a href="#sec4dot3-cancers-10-00184" class="html-sec">Section 4.3</a>).</p> "> Figure 4
<p>Immunohistochemical staining using the RIPK2 phospho-Y474 antibody in IBC breast tissue pre- and post-chemotherapy as indicated. Red scale bar: 50 µm. DAB staining was quantified using ImageJ software and normalized to normal non-neoplastic breast tissue. A total of eight IBC patient tissues pre- and post-chemotherapy were quantified. <span class="html-italic">p</span>-values represent the difference between normal and pre-chemo and post-chemo, respectively.</p> "> Figure 5
<p>Correlation of active RIPK2 expression with: (<b>a</b>) primary tumor stage; (<b>b</b>) presence of distant metastasis stage; (<b>c</b>) cancer stage; and (<b>d</b>) body mass index (BMI) in breast cancer. Active RIPK2 denotes autophosphorylation at site Y474.</p> "> Figure 6
<p>Total RIPK2 mRNA expression in Non-IBC and IBC: (<b>a</b>) cell lines (<span class="html-italic">n</span> = 12) GEO (Gene Expression Omnibus dataset) (GSE40464) [<a href="#B62-cancers-10-00184" class="html-bibr">62</a>] and (<b>b</b>) tumor tissue (<span class="html-italic">n</span> = 40) GEO dataset (GSE45584) [<a href="#B63-cancers-10-00184" class="html-bibr">63</a>] from public breast cancer expression array datasets. IBC cell lines include MDA-IBC-3, MDA-IBC-2, SUM149, and SUM190, non-IBC includes MDA-MB-231, MDA-MB-468. In (<b>b</b>) Non-IBC mainly refers to Luminal A, Luminal B, HER2 overexpressed, and TNBC.</p> "> Figure 7
<p>Correlation of active RIPK2 expression with HER2 mRNA expression: (<b>a</b>) and Ras association domain family protein 1A (<span class="html-italic">RASSF1A</span>) CpG methylation percentage; (<b>b</b>) correlation of <span class="html-italic">RASSF1A</span> mRNA expression and <span class="html-italic">RASSF1A</span> CpG methylation percentage; and (<b>c</b>) in IBC. CpG methylation analysis was carried out as described elsewhere [<a href="#B67-cancers-10-00184" class="html-bibr">67</a>] with focus on 32 CpG residues before the transcriptional start site (32 CpG <span class="html-italic">x</span>-axis label I (<b>b</b>) and CpG 13–32 (20 CpG) from the transcription start site.</p> "> Figure 8
<p>Potential importance of RIPK2 in IBC. IBC cell line and patient samples reveal elevated levels of active RIPK2 that may be linked to epigenetic silencing of RASSF1A. Loss of RASSF1A, therefore, could be a new risk factor in IBC while active RIPK2 may have a role in regulating cellular response to chemotherapy. We speculate that RIPK2 inhibitors may be emerging therapeutic options for IBC.</p> ">
Abstract
:1. Introduction
2. Results
2.1. IBC Cell Lines Exhibit High NF-κB Activity
2.2. Elevated RIPK2 Activity Level in IBC Cell Lines and Patient Tissues
2.3. Neoadjuvant Chemotherapy Does Not Inhibit RIPK2 Activity
2.4. RIPK2 Activity as an Independent Prognostic Marker
3. Discussion
4. Materials and Methods
4.1. Immunoblotting and Antibodies
4.2. Breast Cancer Samples
4.3. Cell Lines
4.4. RIPK2 In Vitro Kinase Assay
4.5. RIPK2 ADP-Glo Kinase Assay (Promega)
4.6. Immunohistochemical and Immunoblot Staining and Evaluation
4.7. Nuclear and Cytoplasmic Extracts
4.8. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Variable | n (%) | Variable | n (%) |
---|---|---|---|
Age | TNBC | ||
≤45 | 11 (22) | Yes | 10 (20) |
>45 | 39 (78) | No | 40 (80) |
Grade | Tumor Size | ||
I | 11 (22) | ≤3 cm | 29 (58) |
III | 35 (70) | >3 cm | 13 (26) |
Unknown | 4 (8) | Unknown | 8 (16) |
ER | PR | ||
Positive | 20 (40) | Positive | 28 (56) |
Negative | 27 (54) | Negative | 19 (38) |
Unknown | 3 (6) | Unknown | 2 (4) |
TNM | HER2 | ||
I | 17 (34) | Positive | 30 (60) |
II | 13 (26) | Negative | 18 (36) |
III | 16 (32) | Unknown | 2 (4) |
IV | 4 (8) |
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Zare, A.; Petrova, A.; Agoumi, M.; Armstrong, H.; Bigras, G.; Tonkin, K.; Wine, E.; Baksh, S. RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis. Cancers 2018, 10, 184. https://doi.org/10.3390/cancers10060184
Zare A, Petrova A, Agoumi M, Armstrong H, Bigras G, Tonkin K, Wine E, Baksh S. RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis. Cancers. 2018; 10(6):184. https://doi.org/10.3390/cancers10060184
Chicago/Turabian StyleZare, Alaa, Alexandra Petrova, Mehdi Agoumi, Heather Armstrong, Gilbert Bigras, Katia Tonkin, Eytan Wine, and Shairaz Baksh. 2018. "RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis" Cancers 10, no. 6: 184. https://doi.org/10.3390/cancers10060184