Suwon Kim

Interests

Research

Cancer Biology, Cancer; Tumor suppressors; Developmental, cell and molecular biology; Gene regulation and epigenetics; Chromatin remodeling; Signaling and steroid biology; Breast cancer therapy resistance and recurrence; Cell differentiation; Diseases of development and aging;

Teaching

Cancer Biology/Oncology

Courses

Scholarly Contributions

Journals/Publications

• Kim, S., & Bagchi, S. (2022). Abstract 2426: GNG4 is a candidate G-proteinγ-subunit downstream of the Cxcl10/Cxcr3 axis that mediates cell migration in breast cancer. Cancer Research, 82(12_Supplement), 2426-2426. doi:10.1158/1538-7445.am2022-2426
• Tsutsumi, E., Stricklin, J., Peterson, E. A., Schroeder, J. A., & Kim, S. (2022). Cxcl10 chemokine induces migration of ING4-deficient breast cancer cells via a novel crosstalk mechanism between the Cxcr3 and Egfr receptors. Molecular and cellular biology, MCB0038221.
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  The chemokine Cxcl10 has been associated with poor prognosis in breast cancer, but the mechanism is not well understood. Our previous study have shown that was repressed by the ING4 tumor suppressor, suggesting a potential inverse functional relationship. We thus investigated a role for Cxcl10 in the context of ING4 deficiencies in breast cancer. We first analyzed public gene expression datasets and found that patients with -high/-low expressing tumors had significantly reduced disease-free survival in breast cancer. , Cxcl10 induced migration of -deleted breast cancer cells, but not of -intact cells. Using inhibitors, we found that Cxcl10-induced migration of -deleted cells required Cxcr3, Egfr, and the Gβγ subunits downstream of Cxcr3, but not Gαi. Immunofluorescent imaging showed that Cxcl10 induced early transient colocalization between Cxcr3 and Egfr in both -intact and -deleted cells, which recurred only in -deleted cells. A peptide agent that binds to the internal juxtamembrane domain of Egfr inhibited Cxcr3/Egfr colocalization and cell migration. Taken together, these results presented a novel mechanism of Cxcl10 that elicits migration of -deleted cells, in part by inducing a physical or proximal association between Cxcr3 and Egfr and signaling downstream via Gβγ. These results further indicated that ING4 plays a critical role in the regulation of Cxcl10 signaling that enables breast cancer progression.
• Kim, S., Tsutsumi, E., Stricklin, J., & Arnold, E. (2021). Abstract 1978: ING4 deficiency results in recurrent crosstalk between Cxcl10/Cxcr3 and Egfr in breast cancer cells. Cancer Research, 81(13_Supplement), 1978-1978. doi:10.1158/1538-7445.am2021-1978
• Peng, S., Hebert, L. L., Eschbacher, J. M., & Kim, S. (2020). Single-Cell RNA Sequencing of a Postmenopausal Normal Breast Tissue Identifies Multiple Cell Types That Contribute to Breast Cancer. Cancers, 12(12).
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  The human breast is composed of diverse cell types. Studies have delineated mammary epithelial cells, but the other cell types in the breast have scarcely been characterized. In order to gain insight into the cellular composition of the tissue, we performed droplet-mediated RNA sequencing of 3193 single cells isolated from a postmenopausal breast tissue without enriching for epithelial cells. Unbiased clustering analysis identified 10 distinct cell clusters, seven of which were nonepithelial devoid of cytokeratin expression. The remaining three cell clusters expressed cytokeratins (CKs), representing breast epithelial cells; Cluster 2 and Cluster 7 cells expressed luminal and basal CKs, respectively, whereas Cluster 9 cells expressed both luminal and basal CKs, as well as other CKs of unknown specificity. To assess which cell type(s) potentially contributes to breast cancer, we used the differential gene expression signature of each cell cluster to derive gene set variation analysis (GSVA) scores and classified breast tumors in The Cancer Gene Atlas (TGGA) dataset ( = 1100) by assigning the highest GSVA scoring cell cluster number for each tumor. The results showed that five clusters (Clusters 2, 3, 7, 8, and 9) could categorize >85% of breast tumors collectively. Notably, Cluster 2 (luminal epithelial) and Cluster 3 (fibroblast) tumors were equally prevalent in the luminal breast cancer subtypes, whereas Cluster 7 (basal epithelial) and Cluster 9 (other epithelial) tumors were present primarily in the triple-negative breast cancer (TNBC) subtype. Cluster 8 (immune) tumors were present in all subtypes, indicating that immune cells may contribute to breast cancer regardless of the subtypes. Cluster 9 tumors were significantly associated with poor patient survival in TNBC, suggesting that this epithelial cell type may give rise to an aggressive TNBC subset.
• Hendricks, W. P., Briones, N., Halperin, R. F., Facista, S., Heaton, P. R., Mahadevan, D., & Kim, S. (2019). PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer. Cancers, 11(10).
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  The therapeutic HER2-targeting antibody trastuzumab has been shown to elicit tumor immune response in a subset of HER2-positive (HER2+) breast cancer. We performed genomic and immunohistochemical profiling of tumors from eight patients who have completed multiple rounds of neoadjuvant trastuzumabb to identify predictive biomarkers for trastuzumab-elicited tumor immune responses. Immunohistochemistry showed that all tumors had an activated tumor immune microenvironment positive for nuclear NF-κB/p65RelA, CD4, and CD8 T cell markers, but only four out of eight tumors were positive for the PD-1 immune checkpoint molecule, which is indicative of an exhausted immune environment. Exome sequencing showed no specific driver mutations correlating with PD-1 positivity. Hierarchical clustering of the RNA sequencing data revealed two distinct groups, of which Group 2 represented the PD-1 positive tumors. A gene expression signature that was derived from this clustering composed of 89 genes stratified HER2+ breast cancer patients in the TCGA dataset and it was named PD-1-Associated Gene Expression Signature in HER2+ Breast Cancer (PAGES-HBC). Patients with the Group 2 PAGES-HBC composition had significantly more favorable survival outcomes with mortality reduced by 83% (hazard ratio 0.17; 95% CI, 0.05 to 0.60; = 0.011). Analysis of three longitudinal samples from a single patient showed that PAGES-HBC might be transiently induced by trastuzumab, independent of clonal tumor expansion over time. We conclude that PAGES-HBC could be further developed as a prognostic predictor of trastuzumab response in HER2+ breast cancer patients and be potentially used as an alternative biomarker for anti-PD-1 therapy trials.
• Snipes, G., Kim, S., Heaton, P., Halperin, R. F., & Grant, M. (2019). Abstract 3425: Mutations in DNA repair and microtubule assembly genes found in triple negative breast tumors treated with neoadjuvant chemotherapy. Cancer Research, 79, 3425-3425. doi:10.1158/1538-7445.am2019-3425
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  Up to 20% of breast cancer is clinically defined as triple-negative breast cancer (TNBC) lacking estrogen, progesterone, and HER2 receptors. Because no targeted therapy is available, cytotoxic chemotherapy is the primary mode of adjuvant TNBC therapy, but is effective in ~30% patients. In order to determine molecular underpinnings of chemotherapy resistance in TNBC, we analyzed 12 TNBC patient tumor samples collected post neoadjuvant chemotherapy using DNA/RNA sequencing. DNA analysis showed two tumors contained TP53 inactivating mutations and two tumors PIK3CA activating mutations. In addition, a number of mutations in the DNA repair pathway genes were identified including XRCC1, XRCC3, and ATXR, suggesting that DNA damaging nature of chemotherapy agents may have enriched these mutations. In addition, we found mutations in the genes involved in microtubule assembly including BUB3 and APC2, suggesting that these gene mutations may confer resistance to taxol, an anti-microtubule chemotherapy agent. RNA sequencing revealed a true heterogeneous nature of TNBE in that unsupervised clustering did not identify any distinct gene signature correlative of chemotherapy resistance. We are currently evaluating phenotypes related to chemotherapy resistance using cells genetically engineered with the BUB3 or APC2 mutations. Citation Format: Michael Grant, George Snipes, Rebecca Halperin, Paul Heaton, Suwon Kim. Mutations in DNA repair and microtubule assembly genes found in triple negative breast tumors treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3425.
• Szeto, E., & Kim, S. (2019). Abstract 3453: CXCL10 contributes to aggressive disease progression in ING4-deficient breast cancer. Cancer Research, 79, 3453-3453. doi:10.1158/1538-7445.am2019-3453
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  CXCL10 is a chemoattractant secreted by various cell types during inflammation for immune cells expressing its cognate receptor CXCR3. In breast cancer, CXCL10 has been associated with increased tumor lymphocytic infiltrates and poor patient prognosis. In addition, pharmacological inhibition of CXCR3 resulted in reduced lung metastases of mammary tumors in mice, suggesting CXCL10/CXCR3 signaling contributes to aggressive breast cancer. We previously identified CXCL10 as an NF-κB target gene repressed by Inhibitor of Growth 4 (ING4) in breast cancer cells. As ING4 deficiencies reported in 34% of breast tumors have been correlated with faster disease recurrence in patients, we investigated a functional interplay between CXCL10 and ING4. First, we assessed the clinical relevance of CXCL10, CXCR3, and/or ING4 expression levels using a public gene expression data set. Second, we genetically engineered T47D breast cancer cells to overexpress or delete the ING4 gene and determined cell phenotypes in the presence or absence of CXCL10 by utilizing cell migration assays and Western blot. Analysis of the GDS806 gene data set showed that patients with tumors expressing high levels of CXCL10 experienced significantly increased rates of disease recurrence while CXCR3 expression did not have a significant effect. The analysis also showed tumors expressing low levels of ING4 expressed higher levels of CXCL10, indicating an inverse expression pattern between the two genes. Moreover, patients with ING4-low/CXCL10-high tumors had a 4-fold faster recurrence rate compared to ING4-high/CXCL10-low tumor patients. These results indicated that high CXCL10 expression contributed to significantly accelerated disease recurrence compounded by low ING4 expression, suggesting a functional relationship between the two genes which may exacerbate tumor phenotypes. While CXCL10 did not affect growth rates of T47D cells with or without ING4, CXCL10 induced migration only in ING4-deleted cells. These results suggested that ING4 inhibited CXCL10 signaling. The western blot analyses showed no change in CXCR3 expression, but elevated phosphorylation of insulin-like growth factor 1 receptor (IGF1R) after CXCL10 treatment, suggesting CXCL10 may signal by activating IGF1R. Consistent with this idea, when cells were treated with an IGF1R inhibitor, Linsitinib (OSI-906), CXCL10-induced migration was attenuated in ING4-deleted cells. In conclusion, these results suggest that in order to promote an aggressive tumor phenotype, CXCL10 induces migration of ING4-deficient tumor cells in part by activating IGF1R. This study reports the first demonstration of the chemokine CXCL10 exerting a direct effect on breast cancer cells and puts forth the CXCL10/IGF1R signaling pathway as a potential therapeutic target for ING4-deficient aggressive breast cancer. Citation Format: Emily Szeto, Suwon Kim. CXCL10 contributes to aggressive disease progression in ING4-deficient breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3453.
• Kim, S. (2018). Tumor suppressor insufficiency: What’s in an expression?. Journal of Molecular Cancer, 3, 15-16.
• Keenen, M. M., & Kim, S. (2016). Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells. Breast cancer (Dove Medical Press), 8, 211-221.
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  Resistance to antiestrogen therapy remains a significant problem in breast cancer. Low expression of inhibitor of growth 4 (ING4) in primary tumors has been correlated with increased rates of recurrence in estrogen receptor-positive (ER+) breast cancer patients, suggesting a role for ING4 in ER signaling. This study provides evidence that ING4 inhibits ER activity. ING4 overexpression increased the sensitivity of T47D and MCF7 ER+ breast cancer cells to hormone deprivation. ING4 attenuated maximal estrogen-dependent cell growth without affecting the dose-response of estrogen. These results indicated that ING4 functions as a noncompetitive inhibitor of estrogen signaling and may inhibit estrogen-independent ER activity. Supportive of this, treatment with fulvestrant but not tamoxifen rendered T47D cells sensitive to hormone deprivation as did ING4 overexpression. ING4 did not affect nuclear ERα protein expression, but repressed selective ER-target gene transcription. Taken together, these results demonstrated that ING4 inhibited estrogen-independent ER activity, suggesting that ING4-low breast tumors recur faster due to estrogen-independent ER activity that renders tamoxifen less effective. This study puts forth fulvestrant as a proposed therapy choice for patients with ING4-low ER+ breast tumors.
• Kim, S. (2015). New and emerging factors in tumorigenesis: an overview. Cancer management and research, 7, 225-39.
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  This article provides an overview of the genes and cellular processes that have emerged recently as new key factors in tumorigenesis. We review these in the context of three broad categories. First, genome-scale sequencing studies have revealed a set of frequently mutated genes in cancer. Genes that are mutated in >5% of all cancers across tissue types are discussed, with a highlighted focus on the two most frequently mutated genes, TP53 and PIK3CA. Second, the mechanisms of resistance to targeted therapy are reviewed. These include acquired resistance under targeted therapy selection owing to mutations and amplification of genes in the same or parallel signaling pathways. Importantly, sequencing of primary tumors has revealed that therapy-resistant clones already exist prior to targeted therapy, demonstrating that tumor heterogeneity in primary tumors confers a mechanism for inherent therapy resistance. Third, "metastasis-specific genes", or rather lack thereof, are discussed. While many genes have been shown to be capable of promoting metastasis in experimental systems, no common genetic alterations have been identified specific to metastatic lesions. Rather, the same gene mutations frequently found in primary tumors are also found prevalent in metastases, suggesting that the genes that drive tumorigenesis may also drive metastasis. In this light, an emerging view of metastatic progression is discussed. Collectively, these recent advances in cancer research have refined our knowledge on cancer etiology and progression but also present challenges that will require innovative new approaches to treat and manage cancer.
• Berger, P. L., Frank, S. B., Schulz, V. V., Nollet, E. A., Edick, M. J., Holly, B., Chang, T. A., Hostetter, G., Kim, S., & Miranti, C. K. (2014). Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis. Cancer research, 74(12), 3357-68.
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  The mechanisms by which Myc overexpression or Pten loss promotes prostate cancer development are poorly understood. We identified the chromatin remodeling protein, ING4, as a crucial switch downstream of Myc and Pten that is required for human prostate epithelial differentiation. Myc-induced transient expression of ING4 is required for the differentiation of basal epithelial cells into luminal cells, while sustained ING4 expression induces apoptosis. ING4 expression is lost in >60% of human primary prostate tumors. ING4 or Pten loss prevents epithelial cell differentiation, which was necessary for tumorigenesis. Pten loss prevents differentiation by blocking ING4 expression, which is rescued by ING4 re-expression. Pten or ING4 loss generates tumor cells that co-express basal and luminal markers, indicating prostate oncogenesis occurs through disruption of an intermediate step in the prostate epithelial differentiation program. Thus, we identified a new epithelial cell differentiation switch involving Myc, Pten, and ING4, which when disrupted leads to prostate tumorigenesis. Myc overexpression and Pten loss are common genetic abnormalities in prostate cancer, whereas loss of the tumor suppressor ING4 has not been reported. This is the first demonstration that transient ING4 expression is absolutely required for epithelial differentiation, its expression is dependent on Myc and Pten, and it is lost in the majority of human prostate cancers. This is the first demonstration that loss of ING4, either directly or indirectly through loss of Pten, promotes Myc-driven oncogenesis by deregulating differentiation. The clinical implication is that Pten/ING4 negative and ING4-only negative tumors may reflect two distinct subtypes of prostate cancer.
• Byron, S. A., Min, E., Thal, T. S., Hostetter, G., Watanabe, A. T., Azorsa, D. O., Little, T. H., Tapia, C., & Kim, S. (2012). Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer. PloS one, 7(10).
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  Nuclear Factor kappa B (NF-κB) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-κB in breast cancer. We surveyed primary breast tumor samples for ING4 protein expression using tissue microarrays and a newly generated antibody. We found that 34% of tumors expressed undetectable to low levels of the ING4 protein (n = 227). Tumors with low ING4 expression were frequently large in size, high grade, and lymph node positive, suggesting that down-regulation of ING4 may contribute to breast cancer progression. In the same tumor set, we found that low ING4 expression correlated with high levels of nuclear phosphorylated p65/RelA (p-p65), an activated form of NF-κB (p = 0.018). Fifty seven percent of ING4-low/p-p65-high tumors were lymph node-positive, indicating a high metastatic tendency of these tumors. Conversely, ectopic expression of ING4 inhibited p65/RelA phosphorylation in T47D and MCF7 breast cancer cells. In addition, ING4 suppressed PMA-induced cell invasion and NF-κB-target gene expression in T47D cells, indicating that ING4 inhibited NF-κB activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-κB-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-κB-target genes in primary breast tumors by analyzing public gene expression datasets. Moreover, low ING4 expression or high expression of the gene signature composed of a subset of ING4-repressed NF-κB-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-κB in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-κB, contributing to tumor progression and reduced disease-free patient survival in breast cancer.
• Kim, S., Miranti, C. K., & Berger, P. L. (2012). Abstract C63: Understanding prostate cancer initiation and development through differentiation: Role of ING4 and Myc in prostate differentiation and cancer development. Cancer Research, 72(4 Supplement), C63-C63. doi:10.1158/1538-7445.prca2012-c63
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  Abstract Introduction: Genes involved in differentiation and cell fate determination are frequently altered in cancers. Understanding how normal differentiation is controlled, and how its deregulation leads to cancer development is paramount to developing better diagnostic and therapeutic strategies for prostate cancer. Our laboratory recently developed an in vitro differentiation model in which human AR-negative basal prostate epithelial cells can be differentiated in to AR-positive secretory cells. Loss of integrin expression and cell-matrix adhesion is crucial to generating stable AR-expressing cells. This is consistent with the observation that integrins are only expressed in basal cells and AR is only expressed in secretory cells. However, in prostate cancer basal cells are lost and AR and integrin α6β1 are co-expressed in the tumor cells. The mechanism by which this occurs is unknown. Our hypothesis is that oncogenic conversion disrupts an intermediate step in normal prostate epithelial differentiation, causing retention of integrin α6β1 and AR expression in the same cell. The earliest alterations in cell adhesion during differentiation are the loss of the extracellular matrix laminin 5 and its respective ligand-specific integrin subunits, α3 and β4. This results in the pairing of the α6 and β1 subunits to generate α6β1, which is not lost until several days later. Several lines of evidence suggest Myc is required to suppress α6β1 expression. Misregulated expression of Myc may contribute to prostate cancer development through up-regulation of integrin α6β1. ING4, a PHD finger containing nuclear protein, is a tumor suppressor that blocks Myc-induced hyperplasia. We hypothesize that ING4 controls Myc, is vital for the normal prostate epithelial differentiation, and loss of ING4 is required for tumorigenesis. Methods: We manipulated Myc and ING4 expression in differentiating human prostate epithelial cells and measured the effects on differentiation. We generated tumorigenic variants by over expressing Myc and Erg, and suppressing Pten. We measured ING4 expression in prostate cancer tissues. Results: Myc over expression resulted in faster differentiation, i.e. loss of integrin expression and induction of AR-responsive genes. However, the differentiated Myc over expressing cells eventually died while control cells did not. ING4 expression increased transiently during differentiation. Loss of ING4 expression did not affect early differentiation; however, cells could not complete differentiation. Myc over expression resulted in an increase in ING4 expression, and ING4 over expression, like Myc, initially augmented differentiation, but induced death of the differentiated cells. Knock-down of ING4 reversed the effect of Myc over expression. Epithelial cells over expressing Myc, Erg, and shPten were tumorigenic in mice, but failed to properly differentiate in vitro. They initiated the AR program, but failed to switch off integrin expression. Over-expression of ING4 in the tumorigenic cells restored normal differentiation. In a cohort of 50 patients, ING4 expression was lost in 67% of primary tumors. Conclusions: These data indicate Myc stimulates ING4 expression in mid differentiation and ING4 is required transiently for proper differentiation and loss of integrin expression. Sustained over expression of ING4, directly or indirectly by Myc, results in death of the differentiated cells. In tumorigenic cells, the differentiation program is altered such that Myc over expression no longer promotes full differentiation, ING4 is not turned on, and cells survive. We hypothesize that ING4 loss is required for prostate cancer development to overcome the death-inducing effects of Myc over expression. Funding: Association for International Cancer Research and VARI. Citation Format: Penny Berger, Suwon Kim, Cindy K. Miranti. Understanding prostate cancer initiation and development through differentiation: Role of ING4 and Myc in prostate differentiation and cancer development [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C63.
• Tapia, C., Zlobec, I., Schneider, S., Kilic, E., Güth, U., Bubendorf, L., & Kim, S. (2011). Deletion of the inhibitor of growth 4 (ING4) tumor suppressor gene is prevalent in human epidermal growth factor 2 (HER2)-positive breast cancer. Human pathology, 42(7).
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  Inhibitor of growth 4 (ING4) is a candidate tumor suppressor gene that was shown to be deleted in 10% to 20% of breast cancers by array comparative genome hybridization analysis. We developed fluorescent in situ hybridization to detect the ING4 gene directly in the tissue samples on tumor tissue microarrays. We evaluated the ING4 gene status in 1033 breast cancer tissue samples and observed that ING4 was deleted in 16.5% (170/1033) of all breast cancers. ING4 deletion was significantly associated with Her2 overexpression: of the tumors with ING4 deletion, 23.8% (39/164) were human epidermal growth factor 2 (HER2) positive, as compared with 14.1% (115/814) of the tumors without ING4 deletion (P = .002). In addition, the tumors with ING4 deletion were more likely to belong to the HER2 molecular subtype (estrogen receptor negative/progesterone receptor negative/human epidermal growth factor positive) of breast cancer, compared with the other subtypes (28.4% HER2 versus 15.7% all, P = .002). ING4 deletion did not affect survival outcome of all patients with breast cancer (P = .797) or of the patients with HER2-positive tumors (P = .792). We conclude that ING4 deletion in breast cancer is relatively common, as 1 in 6 breast cancer harbors ING4 deletion. Furthermore, ING4 deletion is more prevalent in HER2-positive tumors, suggesting a functional antagonistic relationship between the ING4 tumor suppressor and the HER2 oncogene. These results sustain the view that ING4 is a tumor suppressor in breast cancer and suggest that ING4 deletion may contribute to the pathogenesis of HER2-positive breast cancer.
• Whitsett, T. G., & Kim, S. (2011). Abstract 2180: Antagonistic relationship between the tumor suppressor ING4 and estrogen signaling in breast cancer. Cellular and Molecular Biology, 71, 2180-2180. doi:10.1158/1538-7445.am2011-2180
• Whitsett, T. G., Kim, S., & Dempsey, K. J. (2011). Abstract 4024: ING4 tumor suppressor binds to estrogen receptor-complex and modulates estrogen-dependent cell growth and gene expression in breast cancer. Cellular and Molecular Biology, 71, 4024-4024. doi:10.1158/1538-7445.am2011-4024
• Kim, S., Welm, A. L., & Bishop, J. M. (2010). A dominant mutant allele of the ING4 tumor suppressor found in human cancer cells exacerbates MYC-initiated mouse mammary tumorigenesis. Cancer research, 70(12).
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  ING4 is a candidate tumor suppressor gene that is deleted in 10% to 20% of human breast cancers and is mutated in various human cancer cell lines. To evaluate whether ING4 has a tumor-suppressive role in breast tissue, we overexpressed it in mouse mammary glands using a transplant system. Ectopic expression of ING4 suppressed MYC-induced mammary hyperplasia, but not tumorigenesis. In the same model system, we show that a COOH-terminal truncation mutant of ING4 found in human cancer cells could act alone to induce abnormal gland structures resembling mammary hyperplasia, which did not progress to tumors. However, coexpression of the ING4 mutant with MYC increased the penetrance and metastasis of MYC-initiated mammary tumors, giving rise to tumors with more organized acinar structures. Similarly, in vitro expression of the ING4 mutant in MCF10A mammary epithelial cells reinforced tight junctional structures. Our results provide direct functional evidence that ING4 could suppress the early stages of breast cancer and that dominant mutant alleles of ING4 might contribute to malignant development.
• Yang, D., Liu, H., Goga, A., Kim, S., Yuneva, M., & Bishop, J. M. (2010). Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proceedings of the National Academy of Sciences of the United States of America, 107(31).
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  The Myc protein and proteins that participate in mitosis represent attractive targets for cancer therapy. However, their potential is presently compromised by the threat of side effects and by a lack of pharmacological inhibitors of Myc. Here we report that a circumscribed exposure to the aurora kinase inhibitor, VX-680, selectively kills cells that overexpress Myc. This synthetic lethal interaction is attributable to inhibition of aurora-B kinase, with consequent disabling of the chromosomal passenger protein complex (CPPC) and ensuing DNA replication in the absence of cell division; executed by sequential apoptosis and autophagy; not reliant on the tumor suppressor protein p53; and effective against mouse models for B-cell and T-cell lymphomas initiated by transgenes of MYC. Our findings cast light on how inhibitors of aurora-B kinase may kill tumor cells, implicate Myc in the induction of a lethal form of autophagy, indicate that expression of Myc be a useful biomarker for sensitivity of tumor cells to inhibition of the CPPC, dramatize the virtue of bimodal killing by a single therapeutic agent, and suggest a therapeutic strategy for killing tumor cells that overexpress Myc while sparing normal cells.
• Kim, S. (2005). HuntING4 new tumor suppressors. Cell cycle, 4(4).
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  The well-characterized function of many tumor suppressors is to directly regulate cell cycle events. We recently reported a genetic screen to identify genes that suppress loss of contact inhibition but do not inhibit normal cell proliferation. ING4, one of the genes identified by the screen, is frequently mutated in human cancer, suggesting a role for ING4 as a tumor suppressor. ING4 suppresses tumor cell features such as loss of contact inhibition, cell growth in soft agar, and tumor growth in nude mice. ING4 may belong to a class of tumor suppressors whose function is specific to a tumorigenic event that does not directly involve deregulation of the cell cycle. Studies of these tumor suppressors may provide insight into the molecular mechanisms underlying such tumorigenic events.
• Welm, A. L., Kim, S., Welm, B. E., & Bishop, J. M. (2005). MET and MYC cooperate in mammary tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 102(12).
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  In human breast cancer, overexpression of the protooncogene MET is strongly associated with poor prognosis and high risk of metastasis. It stands out as a reliable prognostic indicator of survival and defines a set of tumors exclusive of those that express HER2 or hormone receptors. Studies have shown that overexpression of mutant forms of MET cause cancer in mice. However, MET mutations have not been found in human breast cancer, and the consequences of overexpression of normal MET are unknown. To investigate the role of MET and other putative oncogenes in breast cancer, we developed an experimental system that involves retroviral delivery of genes into primary mammary epithelial cells, followed by transplantation of the transduced cells into mammary fat pads. Using this approach, we found that overexpression of wild-type MET leads to the development of nonprogressive neoplasms. The lesions progressed to mammary adenocarcinoma when a second protooncogene, MYC, was overexpressed, indicating that MET and MYC cooperate in mammary tumorigenesis. Both the nonprogressive neoplasms and adenocarcinomas display characteristics consistent with transformation and expansion of mammary progenitor cells. The approach described here should provide a useful model with which to efficiently test effects of various genes on tumor development in the breast.
• Kim, S., Chin, K., Gray, J. W., & Bishop, J. M. (2004). A screen for genes that suppress loss of contact inhibition: identification of ING4 as a candidate tumor suppressor gene in human cancer. Proceedings of the National Academy of Sciences of the United States of America, 101(46).
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  We have devised a screen for genes that suppress the loss of contact inhibition elicited by overexpression of the protooncogene MYCN. The initial application of this screen detected nine distinctive suppressors within a representative human cDNA library. One of these genes was ING4, a potential tumor suppressor gene that maps to human chromosome 12p13. Ectopic expression of ING4 suppressed the loss of contact inhibition elicited by either MYCN or MYC but had no direct effect on cellular proliferation. Pursuing the possibility that ING4 might be a tumor suppressor gene, we found inactivating mutations in ING4 transcripts from various human cancer cell lines. In addition, we used comparative genomic hybridization to detect deletion of the ING4 locus in 10-20% of human breast cancer cell lines and primary breast tumors. Ectopic expression of ING4 attenuated the growth of T47D human breast cancer cells in soft agar. We conclude that ING4 is a strong candidate as a tumor suppressor gene.
• Kim, S. -., Schilke, B., Craig, E. A., & Horwich, A. L. (1998). Folding in vivo of a newly translated yeast cytosolic enzyme is mediated by the SSA class of cytosolic yeast Hsp70 proteins.. Proc Natl Acad Sci, 22(95), 12860-12865.
• Yan, W., Schilke, B., Pfund, C., Walter, W., Kim, S. -., & Craig, E. A. (1998). Zuotin, a ribosome-associated DnaJ molecular chaperone.. EMBO J, 16(17), 4809-4817.
• Kim, S. -., Willison, K. R., & Horwich, A. L. (1994). Cystosolic chaperonin subunits have a conserved ATPase domain but diverged polypeptide-binding domains.. Trends Biochem Sci, 12(19), 543-548.
• Burmeister, M., Kim, S. -., Price, E. R., de Lange, T., Tantravahi, U., Myers, R. M., & Cox, D. R. (1991). A map of the distal region of the long arm of human chromosome 21 constructed by radiation hybrid mapping and pulsed-field gel electrophoresis.. Genomics, 1(9), 19-30.
• Cox, D. R., Burmeister, M., Price, E. R., Kim, S. -., & Myers, R. M. (1990). Radiation hybrid mapping: a somatic cell genetic method for constructing high-resolution maps of mammalian chromosomes.. Science, 4978(250), 245-250.
• Duyk, G. M., Kim, S. -., Myers, R. M., & Cox, D. R. (1990). Exon trapping: a genetic screen to identify candidate transcribed sequences in cloned mammalian genomic DNA.. Proc Natl Acad Sci U S A, 22(87), 8995-8999.

Proceedings Publications

• Mahadevan, D., Kim, S., Hendricks, W., Heaton, P., Halperin, R., Facista, S., & Briones, N. (2019). Abstract 3412: Genomic signature of trastuzumab neoadjuvant therapy predictive of patient survival in HER2-positive breast cancer. In Molecular and Cellular Biology / Genetics.

Presentations

• Byron, S. A., Min, E., Thal, T. S., Tapia, C., Hoste, G., Watanabe, A., Azorsa, D. O., Little, T. H., & Kim, S. -. (2011, Spring). Down-regulation of NFkB by the ING4 tumor suppressor in breast cancer.. TGen/VARI Scientific Retreat. Phoenix, AZ.
• Dempsey, K. J., Bryon, S. A., Whitsett, T. G., & Kim, S. -. (2011, Spring). The ING4 tumor suppressor binds to the estrogen receptor-transcriptional complex and facilitates tamoxifen response in breast cancer.. Mechanisms and Models of Cancer Meeting, Salk Institute. La Jolla, CA.
• Hernandez, F., Nasser, S., Stone, A., Cunliffe, H. E., Byron, S., Kim, S., & Kim, S. -. (2011, Spring). CytoBasin: A network query and visualization software for basin.. TGen/VARI Scientific Retreat. Phoenix, AZ.
• Kim, S. -., Dempsey, K. J., Byron, S. A., Whitsett, T. G., Little, T. H., Azorsa, D. O., Watanabe, A. T., & Hostetter, G. (2011, Spring). The ING4 tumor suppressor in tamoxifen response in breast cancer.. TGen/VARI Scientific Retreat. Phoenix, AZ.
• Min, E., Byron, S. A., Ellig, M., Tokuyama, M., Dempsey, K., & Kim, S. -. (2011, Spring). Effect of the NFkB inhibitor, parthenolide, on tamoxifen sensitivity in estrogen receptor-positive breast cancer cells with reduced ING4 levels.. TGen/VARI Scientific Retreat. Phoenix, AZ.
• Miranti, C. K., Berger, P., & Kim, S. -. (2011, Spring). Understanding prostate cancer initiation and development through differentiation: Role of ING4 and Myc in prostate differentiation and cancer development.. TGen/VARI Scientific Retreat. Phoenix, AZ.
• Dempsey, K., Whitsett, T., & Kim, S. -. (2010, Spring). ING4 tumor suppressor binds to a transcription co-activator, CCAR1, and modulates estrogen-dependent cell growth and gene expression.. 101st Annual Meeting of the American Association for Cancer Research. Washington, DC.
• Dempsey, K., Whitsett, T., & Kim, S. -. (2010, Spring). ING4 tumor suppressor binds to a transcription co-activator, CCAR1, and modulates estrogen-dependent cell growth and gene expression.. TGen/VARI Scientific Retreat. Phoenix, AZ.
• Dempsey, K., Whitsett, T., & Kim, S. -. (2010, Spring). ING4 tumor suppressor binds to a transcription co-activator, CCAR1, and modulates estrogen-dependent cell growth and gene expression.. Van Andel Research Institute Scientific Retreat. Crystal Springs, MI.
• Raymond-Whish, S., & Kim, S. -. (2010, Spring). ING4 attenuates breast cancer cell growth in Matrigel by altering Wnt/beta-catenin signaling pathway.. 101st Annual Meeting of the American Association for Cancer Research. Washington, DC.
• Raymond-Whish, S., & Kim, S. -. (2010, Spring). ING4 attenuates breast cancer cell growth in matrigel by altering Wnt signaling pathway.. TGen/VARI Scientific Retreat. Phoenix, AZ.
• Whitsett, T. G., & Kim, S. -. (2010, Spring). Antagonistic relationship between the tumor suppressor ING4 and estrogen signaling in breast cancer.. TGen/VARI Scientific Retreat. Phoenix, AZ.
• Tapia, C., Kilic, E., Zlobec, I., Bubendorf, L., & Kim, S. -. (2009, Spring). ING4 deletion in breast cancer: a clinical-pathological correlation.. 100th Annual Meeting of the American Association for Cancer Research. Denver, CO.
• Kim, S. -., Welm, A. L., & Bishop, j. M. (2008, Spring). Oncogenic transformation of the ING4 tumor suppressor: A truncation mutant of ING4 contributes to the MYC-initiated mouse mammary tumorigenesis in part by establishing tight junction structure.. Keystone Symposia. Taos, NM.
• Raymond-Whish, S., & Kim, S. -. (2008, Spring). Transcriptional regulation of kallikrein 7 tissue protease by the ING4 tumor suppressor in breast cancer.. TGen Scientific Retreat. Phoenix, AZ.
• Whitsett, T. G., & Kim, S. -. (2008, Spring). Down-regulation of the ING4 tumor suppressor gene by estrogen in breast cancer cells.. TGen Scientific Retreat. Phoenix, AZ.
• Kim, S. -., Welm, A. L., & Bishop, J. M. (2007, Spring). Oncogenic transformation of the ING4 tumor suppressor.. Translational Genomics Research Institute Scientific Retreat. Phoenix, AZ.

Poster Presentations

• Kim, S., & Bagchi, S. (2022, April). GNG4 is a candidate G-protein γ-subunit downstream of the Cxcl10/Cxcr3 axis that mediates cell migration in breast cancer. AACR annual meeting. New Orleans: AACR.
• Kim, S., & Tsutsumi, E. (2022, April). Cxcl10-induced migration of ING4-deficient breast cancer cells requires periodic recurrent formation of the Cxcr3/Egfr receptor complex. AACR annual meeting. New Orleans: AACR.
• Kim, S., Tsutsumi, E., Stricklin, J., & Peterson, E. (2021, 03/Spring). ING4 deficiency results in recurrent crosstalk between Cxcl10/Cxcr3 and Egfr in breast cancer cells. American Association for Cancer Reseach (AACR) Annual meeting. Virtual: AACR.
• Kim, S. (2019, March). Genomic signature of trastuzumab neoadjuvant therapy predictive of patient survival in HER2-positive breast cancer. ABRC Research Conference. UACOM-Phoenix, AZ: ABRC/Flinn Foundation.
• Kim, S. (2019, October). Gene mutations and enriched immune components in chemotherapy resistance and aggressive tumor progression in triple negative breast cancer. Baylor Scott White Research Institute Scientific Retreat. Charles A Sammons Cancer Center, Dallas TX: Baylor Scott White Research Institute.
• Kim, S. (2019, October). Targeting the ROR-gt/IL-17 Pathway in Colon Cancer: Single cell analysis. Baylor Scott White Research Institute Scientific Retreat. Charles A Sammons Cancer Center, Dallas TX: Baylor Scott White Research Institute.
• Kim, S., & Szeto, E. (2019, March 29-April 3). CXCL10 contributes to Aggressive Disease Progression in ING4-deficient Breast Cancer. AACR American Association for Cancer Research 2019 Annual Meeting. Georgia World Conference Center, Georgia, Atlanta: AACR.
• Kim, S., Grant, M., Snipes, G., Heaton, P., & Halperin, R. (2019, March 29-April 3). Mutations in DNA repair and microtubule assembly genes found in triple negative breast tumors treated with neoadjuvant chemotherapy. AACR American Association for Cancer Research 2019 Annual Meeting. Georgia World Conference Center, Georgia, Atlanta: AACR.
• Kim, S., Hendricks, W., Mahadevan, D., Heaton, P., Halperin, R., Facista, S., & Briones, N. (2019, March 29-April 3). Genomic signature of trastuzumab neoadjuvant therapy predictive of patient survival in HER2-positive breast cancer. AACR American Association for Cancer Research 2019 Annual Meeting. Georgia World Conference Center, Georgia, Atlanta: AACR.
• Kim, S., Peng, S., Hebert, L., & Eschbacher, J. (2019, January 13–17). Single Cell Analysis of the normal breast tissue reveals a novel cell type of which gene signature correlates with poor prognosis in breast cancer. Keystone Symposia in Breckenridge Single Cell Biology. Beaver Run Resort | Breckenridge, Colorado: Keystone Symposia.
• Kim, S., & Szeto, E. (2018, September 28). CXCL10 Mediates Aggressive Disease Progression in ING4-Deficient Breast Cancer. UA Cancer Center Annual Scientific Retreat. Westward Look Resort, Tucson, Arizona: University Arizona Cancer Center.
• Kim, S., Facista, S., Mahadevan, D., Hendricks, W., Heaton, P., & Tassone, E. (2018, March). Identification of immunomodulatory genetic aberrations underlying breast cancer recurrence. 3rd Annual ABRC Research Conference. COM-Phoenix, Phoenix, Arizona: ABRC and Flinn Foundation.
• Kim, S., Grant, M., Snipes, G., Halperin, R., Heaton, P., & Stricklin, J. (2018, November 3). The Tumor-initiated immune microenvironment as a mechanism of chemotherapy resistance in triple-negative breast cancer. BSWRI – TGen Scientific Retreat Fall 2018. Baylor Charles A. Sammons Cancer Center, Dallas, Texas: BSWRI – TGen.
• Kim, S., Khare, P., Sears, C. L., Peng, S., Stricklin, J., Keats, J., Fleshman, J., & Poojary, V. (2018, November 3). Targeting the ROR-gt/IL-17 pathway in colon can. BSWRI – TGen Scientific Retreat Fall 2018. Baylor Charles A. Sammons Cancer Center, Dallas, Texas.
• Kim, S., Lee, Y., & Inge, L. (2018, March). Pro-tumor immune microenvironment resulting from LKB1 and ING4 deficiencies in KRAS-driven non-small cell lung cancer. 3rd Annual ABRC Research Conference. COM-Phoenix, Phoenix, Arizona: ABRC and Flinn Foundation.
• Kim, S., Szeto, E., Arnold, E., Heaton, P., & Stricklin, J. (2018, September). CXCL10 Mediates Aggressive Disease Progression in ING4-deficient Breast Cancer. UA Cancer Center Scientific Retreat. Tucson, AZ: Unversity of Arizona Cancer Center.
• Kim, S., Wohlar, K., & Yoo, C. (2018, October 14 - 17). A Novel In Silico Approach to Identify Gene Signatures Associated with Recurrent Cancer. 30th Anniversary AACR Special Conference Convergence: Artificial Intelligence, Big Data, and Prediction in Cancer. Newport, Rhode Island, USA: American Association for Cancer Research (AACR).
• Kim, S., & Keenen, M. (2017, January). ING4 tumor suppressor in breast cancer: a selective chromatin reader and a modifier. Keystone Symposium. Seattle, WA: Keystone Symposium.
• Kim, S., & Kim, S. (2017, July). Role of ING4 in the estrogen sensitivity of ER+ breast cancer. Helios Symposium. Phoenix, Arizona: Translational Genomic Research Institute/Helios Educational Foundation.
• Kim, S., & Ungor, A. (2017, July). ING4 tumor suppressor and chemotherapy response in triple-negative breast cancer. Helios Symposium. Phoenix, Arizona: Translational Genomic Research Institute/Helios Educational Foundation.
• Kim, S., Eschbacher, J., & Hebert, L. (2017, October). Single cell analysis to identify therapy-resistant breast cancer. University of Arizona Cancer Center Phoenix Scientific Symposium. Phoenix, Arizona: UA Cancer Center.
• Kim, S., Inge, L., & Lee, Y. (2017, March). Pro-tumor immune microenvironment resulting from LKB1 and ING4 deficiencies in KRAS-driven non-small cell lung cancer. 2nd Annual ABRC Research Conference. Phoenix, Arizona: ABRC/VRP/Flinn Foundation.
• Kim, S., Stricklin, J., & Ungor, A. (2017, November). The Tumor Suppressor ING4 Modulates Doxorubicin Resistance in Triple Negative Breast Cancer. Translational Genomic Research Institute Scientific Retreat. Phoenix, Arizona: Translational Genomic Research Institute.
• Kim, S., Byron, S., deMello, D., & Simmons, M. (2016, April). New molecular target to treat MYCN-amplified aggressive neuroblastoma. UA Cancer Center retreat. Tucson, AZ: UA Cancer Center.
• Kim, S., & Keenen, M. M. (2015, June). ING4 inhibits estrogen-independent estrogen receptor signaling in breast cancer cells. BMS symposium. UACOM-Phoenix: BMS department, UACOM-P.
• Kim, S., & Keenen, M. M. (2015, October). ING4 inhibits estrogen-independent estrogen receptor signaling in breast cancer cells. TGen Scientific Retreat. Phoenix Convention Center, Phoenix: Translational Genomics Research Institute.
• Kim, S., Byron, S. A., & Simmons, M. (2015, June). New molecular target to treat MYCN-amplified aggressive neuroblastoma. BMS symposium. UACOM-Phoenix: BMS department, UACOM-P.
• Byron, S., Simons, M., & Kim, S. -. (2013, Fall). New molecular target to treat MYCN-amplified aggressive neuroblastoma.. TGen Scientific Retreat. Phoenix, AZ.
• Dempsey, K., Whitsett, T. G., & Kim, S. -. (2011, Spring). ING4 tumor suppressor binds to estrogen receptor complex and modulates estrogen cell-dependent growth and gene expression in breast cancer.. 102nd Annual Meeting of the American Association for Cancer Research. Orlando, FL.
• Kim, S. -., & Whitsett, T. G. (2011, Spring). Antagonistic relationship between the tumor suppressor ING4 and estrogen signaling in breast cancer.. 102nd Annual Meeting of the American Association for Cancer Research. Orlando, FL.
• Tapia, C., Bubendorf, L., & Kim, S. -. (2008, Spring). Diagnostic FISH for ING4 deletion in breast cancer.. Translational Genomics Research Institute Scientific Retreat. Phoenix, AZ.