Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3) have been investigated as triple-negative breast cancer (TNBC) biomarkers. Reduced EGFR levels can be compensated by increases in HER3; thus, assaying EGFR and HER3 together may improve prognostic value. In a multi-institutional cohort of 510 TNBC patients, we analyzed the impact of HER3, EGFR, or combined HER3-EGFR protein expression in pre-treatment samples on breast cancer-specific and distant metastasis-free survival (BCSS and DMFS, respectively). A subset of 60 TNBC samples were RNA-sequenced using massive parallel sequencing. The combined HER3-EGFR score outperformed individual HER3 and EGFR scores, with high HER3-EGFR score independently predicting worse BCSS (Hazard Ratio [HR] = 2.30, p = 0.006) and DMFS (HR = 1.78, p = 0.041, respectively). TNBCs with high HER3-EGFR scores exhibited significantly suppressed ATM signaling and differential expression of a network predicted to be controlled by low TXN activity, resulting in activation of EGFR, PARP1, and caspases and inhibition of p53 and NFκB. Nuclear PARP1 protein levels were higher in HER3-EGFR-high TNBCs based on immunohistochemistry (p = 0.036). Assessing HER3 and EGFR protein expression in combination may identify which adjuvant chemotherapy-treated TNBC patients have a higher risk of treatment resistance and may benefit from a dual HER3-EGFR inhibitor and a PARP1 inhibitor.

The absence of a robust risk stratification tool for triple negative breast cancer (TNBC) underlies imprecise and nonselective treatment of these patients with cytotoxic chemotherapy. This study aimed to interrogate transcriptomes of TNBC resected samples using next generation sequencing to identify novel biomarkers associated with disease outcomes. A subset of cases (n = 112) from a large, well-characterized cohort of primary TNBC (n = 333) were subjected to RNA-sequencing. Reads were aligned to the human reference genome (GRCH38.83) using the STAR aligner and gene expression quantified using HTSEQ. We identified genes associated with distant metastasis-free survival and breast cancer-specific survival by applying supervised artificial neural network analysis with gene selection to the RNA-sequencing data. The prognostic ability of these genes was validated using the Breast Cancer Gene-Expression Miner v4. 0 and Genotype 2 outcome datasets. Multivariate Cox regression analysis identified a prognostic gene signature that was independently associated with poor prognosis. Finally, we corroborated our results from the two-gene prognostic signature by their protein expression using immunohistochemistry. Artificial neural network identified two gene panels that strongly predicted distant metastasis-free survival and breast cancer-specific survival. Univariate Cox regression analysis of 21 genes common to both panels revealed that the expression level of eight genes was independently associated with poor prognosis (p < 0.05). Adjusting for clinicopathological factors including patient's age, grade, nodal stage, tumor size, and lymphovascular invasion using multivariate Cox regression analysis yielded a two-gene prognostic signature (ACSM4 and SPDYC), which was associated with poor prognosis (p < 0.05) independent of other prognostic variables. We validated the protein expression of these two genes, and it was significantly associated with patient outcome in both independent and combined manner (p < 0.05). Our study identifies a prognostic gene signature that can predict prognosis in TNBC patients and could potentially be used to guide the clinical management of TNBC patients.

E-cadherin is a tumor suppressor gene in invasive lobular breast cancer. However, a proportion of high-grade ductal carcinoma shows reduced/loss of E-cadherin. In this study, we assessed the underlying mechanisms and molecular implications of E-cadherin loss in invasive ductal carcinoma. This study used large, well-characterized cohorts of early-stage breast cancer-evaluated E-cadherin expression via various platforms including immunohistochemistry, microarray analysis using Illumina HT-12 v3, copy number analysis using Affymetrix SNP 6.0 arrays, and next-generation sequencing for differential gene expression. Our results showed 27% of high-grade invasive ductal carcinoma showed reduced/loss of E-cadherin membranous expression. CDH1 copy number loss was in 21% of invasive ductal carcinoma, which also showed low CDH1 mRNA expression (p = 0.003). CDH1 copy number was associated with copy number loss of TP53, ATM, BRCA1, and BRCA2 (p < 0.001). Seventy-nine percent of invasive ductal carcinoma with reduced CDH1 mRNA expression showed elevated expression of E-cadherin transcription suppressors TWIST2, ZEB2, NFKB1, LLGL2, CTNNB1 (p < 0.01). Reduced/loss E-cadherin expression was associated with differential expression of 2143 genes including those regulating Wnt (FZD2, GNG5, HLTF, WNT2, and CER1) and PIK3-AKT (FGFR2, GNF5, GNGT1, IFNA17, and IGF1) signaling pathways. Interestingly, key genes differentially expressed between invasive lobular carcinoma and invasive ductal tumors did not show association with E-cadherin loss in invasive ductal carcinoma. We conclude that E-cadherin loss in invasive ductal carcinoma is likely a consequence of genomic instability occurring during carcinogenesis. Potential novel regulators controlling E-cadherin expression in invasive ductal carcinoma warrant further investigation.

PurposeAndrogen receptor (AR) and AR signaling pathways are thought to play a role in breast cancer (BC) and are potentially related to treatment responses and outcomes. Ankyrin 3 (ANK3) is associated with AR stability in cancer cells. In the present study, we investigated the clinicopathological utility of ANK3 expression with emphasis on AR and its associated signalling pathway at transcriptomic and proteomic phases.Patients and methodsThe Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n=1980) and The Cancer Genome Atlas (TCGA) dataset (n=1039) were used to assess the expression and significance of ANK3 mRNA and other AR signalling pathway-associated gene signature. Using immunohistochemistry, ANK3 protein expression was evaluated in large (n=982) cohort of early-stage BC with long-term follow-up and compared with clinicopathological characteristics and its prognostic value in the whole cohort and the subgroups stratified by AR protein expression.ResultsAn AR-related gene signature was developed, comprising 20 genes, which included ANK3. This AR-related gene signature was significantly associated with AR mRNA expression, oestrogen receptor, human epidermal growth factor receptor 2 (HER2) status and the patients' outcomes. In tumours with high AR protein expression (n=614), high ANK3 protein expression was significantly associated with progesterone receptor positivity and it was independently associated with the good outcomes (p=0.025).ConclusionsThis study indicates that ANK3 is related to AR signalling pathway and is associated with BC prognosis.

Background Lymphovascular invasion (LVI) is associated with the development of metastasis in invasive breast cancer (BC). However, the complex molecular mechanisms of LVI, which overlap with other oncogenic pathways, remain unclear. This study, using available large transcriptomic datasets, aims to identify genes associated with LVI in early-stage BC patients. Methods Gene expression data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort ( n = 1565) was used as a discovery dataset, and The Cancer Genome Atlas (TCGA; n = 854) cohort was used as a validation dataset. Key genes were identified on the basis of differential mRNA expression with respect to LVI status as characterised by histological review. The relationships among LVI-associated genomic subtype, clinicopathological features and patient outcomes were explored. Results A 99-gene set was identified that demonstrated significantly different expression between LVI-positive and LVI-negative cases. Clustering analysis with this gene set further divided cases into two molecular subtypes (subtypes 1 and 2), which were significantly associated with pathology-determined LVI status in both cohorts. The 10-year overall survival of subtype 2 was significantly worse than that of subtype 1. Conclusion This study demonstrates that LVI in BC is associated with a specific transcriptomic profile with potential prognostic value.

Neighborhoods encompass complex environments comprised of unique economic, physical, and social characteristics that have a profound impact on the residing individual's health and, collectively, on the community's wellbeing. Neighborhood disadvantage (ND) is one of several factors that prominently contributes to racial breast cancer (BC) health disparities in American women. African American (AA) women develop more aggressive breast cancer features, such as triple-negative receptor status and more advanced histologic grade and tumor stage, and suffer worse clinical outcomes than European American (EA) women. While the adverse effects of neighborhood disadvantage on health, including increased risk of cancer and decreased longevity, have recently come into focus, the specific molecular mechanisms by which neighborhood disadvantage increases BC risk and worsens BC outcomes (survivorship, recurrence, mortality) are not fully elucidated. This review illuminates the probable biological links between neighborhood disadvantage and predominantly BC risk, with an emphasis on stress reactivity and inflammation, epigenetics and telomere length in response to adverse neighborhood conditions.

Recently, Georgia State University’s Centennial Hall was the premier location for the 2017 International Conference on Triple Negative Breast Cancer (TNBC): Illuminating Actionable Biology, which was held from Sept. 18 to 20, 2017, in Atlanta, USA. The conference featured a stellar line-up of domestic and international speakers and diverse participants including TNBC survivors, luminaries in breast cancer research, medical students and fellows, clinicians, translational researchers, epidemiologists, biostatisticians, bioinformaticians, and representatives from the industry. This report distills the burning questions that spiked the event and summarizes key themes, findings, unique opportunities and future directions that emerged from this confluence of thought leaders.

Abstract Background: Centrosome amplification (CA) which refers to presence of supernumerary or abnormally large centrosomes drives tumor progression by promoting chromosomal instability and the generation of aggressive tumor clones. Although the role of CA in cancer progression is well-defined, no studies have yet discussed how CA is induced in tumor cells. We report here that intra-tumoral hypoxia, which is considered one of the major contributors to intratumor heterogeneity, induces CA via HIF-1α. Methods: We first immunohistochemically labeled 24 breast carcinoma and uninvolved adjacent normal tissue samples for HIF-1α and calculated weighted indices (WIs) for nuclear HIF-1α. Adjacent serial sections from the same tumors were also immunofluorescently labeled for γ-tubulin and CA was calculated. Using public microarray datasets (Kao dataset, n=327), we investigated whether centrosomal gene expression is enriched in breast tumors characterized by a hypoxia gene expression signature. Finally, to determine the role of hypoxia in CA induction we exposed cultured TNBC cells (MDA-MB-231 and MDA-MB-468) to hypoxia and overexpressed (OE) and knocked out (KO) HIF-1α in TNBC cells and quantitated CA. Additionally, to discern the biological pathway through which HIF-1α induces CA we performed ChIP assay and in silico analyses to identify the possible targets of HIF-1α. Results: A strong positive correlation between nuclear HIF-1α WI and CA was found in breast tumor samples (Spearman's rho p=0.722, p<0.001). In addition, we found that higher nuclear HIF-1α was associated with worse overall survival (p=0.041; HR=1.03). Our in silico findings suggest that breast tumors with high expression of hypoxia-associated genes exhibited higher expression of centrosomal genes than breast tumors with low expression of hypoxia-associated genes. In addition, cells cultured in hypoxic conditions exhibited ˜1.5 fold higher (p<0.05) CA when compared to the cells cultured in normoxic conditions. Interestingly level of CA decreased when HIF-1α KO TNBC cells were exposed to hypoxia and it increased when HIF-1α OE TNBC cells were culture in normoxic conditions. Furthermore, we discovered that HIF-1α induced CA by directly regulating the expression of Plk4 which was confirmed by performing ChIP assay. Our results indicated HIF-1α interaction with the motif in the PLK4 promoter from genomic DNA of MDA-MB 231 cells under hypoxic conditions, was significantly (p=0.04) higher when compared with the cells cultured under normoxic conditions. Plk4 mRNA expression was assessed using the online BC gene expression data sets (n=25). We found significantly higher expression of Plk4 in TNBC (n=374) when compared with non-TNBC (n=4098) and it was associated with poor overall survival (HR=1.76; p=0.054) in TNBC. Conclusion: Collectively our findings suggest that hypoxia drives CA in TNBC via HIF-1α and contribute to poor outcomes. Thus, determination of CA and HIF-1α can help risk stratification in TNBC patients for more personalized treatments. Citation Format: Mittal K, Choi DH, Maganti N, Ogden A, Melton BD, Kaur J, Gupta MV, Jonsdottir K, Janseen EAM, Aleskandarany MA, Rakha EA, Rida PCG, Aneja R. Hypoxia induced centrosome amplification via HIF-1α/Plk4 signaling axis associates with poorer overall survival in TNBC [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-23.

Nuclear KIFC1 (nKIFC1) predicts worse outcomes in breast cancer, but its prognostic value within racially distinct triple-negative breast cancer (TNBC) patients is unknown. Thus, nKIFC1 expression was assessed by immunohistochemistry in 163 African American (AA) and 144 White TNBC tissue microarrays (TMAs) pooled from four hospitals. nKIFC1 correlated significantly with Ki67 in White TNBCs but not in AA TNBCs, suggesting that nKIFC1 is not merely a surrogate for proliferation in AA TNBCs. High nKIFC1 weighted index (WI) was associated with significantly worse overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) (Hazard Ratios [HRs] = 3.5, 3.1, and 3.8, respectively; P = 0.01, 0.009, and 0.007, respectively) in multivariable Cox models in AA TNBCs but not White TNBCs. Furthermore, KIFC1 knockdown more severely impaired migration in AA TNBC cells than White TNBC cells. Collectively, these data suggest that nKIFC1 WI an independent biomarker of poor prognosis in AA TNBC patients, potentially due to the necessity of KIFC1 for migration in AA TNBC cells.

Centrosome aberrations (CA) and abnormal mitoses are considered beacons of malignancy. Cancer cell doubling times in patient tumors are longer than in cultures, but differences in CA between tumors and cultured cells are uncharacterized. We compare mitoses and CA in patient tumors, xenografts, and tumor cell lines. We find that mitoses are rare in patient tumors compared with xenografts and cell lines. Contrastingly, CA is more extensive in patient tumors and xenografts (~35–50% cells) than cell lines (~5–15%), although CA declines in patient-derived tumor cells over time. Intratumoral hypoxia may explain elevated CA in vivo because exposure of cultured cells to hypoxia or mimicking hypoxia pharmacologically or genetically increases CA, and HIF-1α and hypoxic gene signature expression correlate with CA and centrosomal gene signature expression in breast tumors. These results highlight the importance of utilizing low-passage-number patient-derived cell lines in studying CA to more faithfully recapitulate in vivo cellular phenotypes.

1100 Background: Recent studies show strong correlation between tumor infiltrating lymphocytes (TILs) and triple-negative breast cancer (TNBC) patient survival. CD8+ T cells serve as a favorable prognostic marker for TNBC. In addition, other cells such as CD4+ T cells, macrophages, B cells, and Tregs also infiltrate tumors. In this study, we delineate a strong relationship between the cycling kinetics of proliferating cells in TNBCs and antitumor immune response. Methods: A multi-institutional study performed by our group has previously shown that KAMS (Ki67-Adjusted Mitotic Score) provides a measure of the cycling kinetics of proliferating tumor cells and robustly stratifies TNBC patients into slow cycling (low KAMS) cyclophosphamide-methotrexate-fluorouracil (CMF)-responsive and fast cycling (high KAMS) CMF-resistant subgroups. In this study, we reviewed clinical data from 124 CMF-treated TNBC patients from Nottingham Hospital and sought correlations between cycling kinetics (High/Low KAMS) and tumor infiltrating immune cells. Results: We found that slow cycling TNBCs had higher mean expression of tumor infiltrating immune cells than fast cycling TNBCs. Intratumoral CD68 (p = 0.003), CD3 (p = 0.006), CD20 (p = 0.01), FOXP3 (p = 0.01), and total numbers of intratumoral and stromal CD68 (p = 0.01) and CD3 (p = 0.03) expressing cells were found to be significantly higher in low KAMS tumors than in high KAMS tumors. Of these biomarkers, CD68 was significantly associated with patients’ breast cancer-specific survival (BCSS): (a) low KAMS, high CD68 TNBCs had better BCSS than low KAMS, low CD68 (p = 0.01) TNBCs, and (b) high KAMS, low CD68 cases had better BCSS than high KAMS, high CD68 cases. Conclusions: Our observation that there are more TILs in slow cycling TNBCs suggests that there may be a dynamic cross-regulation between cycling kinetics and antitumor immune response. From our surprising observation that CD68 exerts polar roles in low/high KAMS subgroups, we propose that distinctions in M1 and M2 macrophage subsets in slow and fast cycling TNBCs may correlate with distinct outcomes. In addition, metabolic competition between tumor and immune cells may determine the level and function of TILs.

Centrosome amplification (CA) is a hallmark of cancer, observable in ≥75% of breast tumors. CA drives aggressive cellular phenotypes such as chromosomal instability (CIN) and invasiveness. Thus, assessment of CA may offer insights into the prognosis of breast cancer and identify patients who might benefit from centrosome declustering agents. However, it remains unclear whether CA is correlated with clinical outcomes after adjusting for confounding factors. To gain insights, we developed a signature, "CA20", comprising centrosome structural genes and genes whose dysregulation is implicated in inducing CA. We found that CA20 was a significant independent predictor of worse survival in two large independent datasets after adjusting for potentially confounding factors. In multivariable analyses including both CA20 and CIN25 (a gene expression-based score that correlates with aneuploidy and has prognostic value in many types of cancer), only CA20 was significant, suggesting CA20 captures the risk-predictive information of CIN25 and offers information beyond it. CA20 correlated strongly with CIN25, so a high CA20 score may reflect tumors with high CIN and potentially other aggressive features that may require more aggressive treatment. Finally, we identified processes and pathways differing between CA20-low and high groups that may be valuable therapeutic targets.

e23170 Background: Centrosome amplification (CA) which refers to presence of supernumerary or abnormally large centrosomes is believed to drive tumor progression by promoting chromosomal instability and the generation of aggressive tumor clones that are more capable of rapid metastasis. Not much is known about factors that drive CA within solid tumors. We have previously shown the existence of rampant CA in triple-negative breast cancers (TNBCs).We report here thatintratumoral hypoxia, which is one of the major contributors to tumor heterogeneity, induces CA in TNBCs via HIF-1α. Methods: We immunohistochemically labeled 24 TNBC and adjacent normal tissue samples for HIF-1α and derived weighted indices (WIs) for nuclear HIF-1α. Adjacent serial sections from the same tumors were immunofluorescently labeled for the centrosomal marker γ-tubulin and CA was determined. Using public microarray datasets (Kao dataset, n = 327), we investigated whether centrosomal gene expression is enriched in breast tumors characterized by a hypoxia gene expression signature. Finally, to test the role of hypoxia in CA induction we exposed cultured TNBC cells (MDA-MB-231 and MDA-MB-468) to hypoxia and overexpressed (OE) or knocked out (KO) HIF-1α and quantitated CA. Results: A strong positive correlation was found between nuclear HIF-1α WI and CA in TNBC samples (Spearman’s rho p = 0.722, p < 0.001), and higher nuclear HIF-1α was associated with worse overall survival (p = 0.041; HR = 1.03). Furthermore, breast tumors with high expression of hypoxia-associated genes exhibited higher expression of centrosomal genes than breast tumors with low expression of hypoxia-associated genes. TNBC cells cultured in hypoxic conditions exhibited ~1.5 fold higher (p < 0.05) CA compared to cells cultured in normoxic conditions. Interestingly, level of CA decreased when HIF-1α KO TNBC cells were exposed to hypoxia; conversely, CA increased when HIF-1α OE TNBC cells were cultured in normoxic conditions. Conclusions: Thus,intratumoral hypoxia drives CA in TNBC via HIF-1α and contributes to poor outcomes. Determination of CA may help identify TNBC patients who could benefit from centrosome declustering drugs and HIF-1α inhibitors.

11612 Background: Limited preclinical evidence suggests that the ErbB family member HER3 may have prognostic value in TNBC. However, HER3 is a pseudokinase that cannot homodimerize, so in order to signal it must bind to other ErbB family members such as HER2 or EGFR. EGFR is frequently overexpressed in TNBC; consequently, it may be necessary to consider HER3 levels in the context of EGFR levels in TNBC to derive clinically meaningful insights. Methods: Towards this end, we tested the prognostic value of a combined immunohistochemical HER3-EGFR score (the sum of the individual H-scores, with the median used as a cutpoint) in a multi-institutional study of n = 510 TNBC patients using Cox proportional hazards regression. We also compared the HER3-EGFR-high and low groups in terms of 105 immunohistochemical biomarkers using Mann-Whitney U tests as well as Ingenuity canonical pathways using gene expression data from RNA-seq. Results: Among chemotherapy-treated TNBC patients, high HER3-EGFR score conferred a 2.30-fold increased risk of dying from breast cancer and a 1.78-fold increased risk of distant metastasis (p = 0.006 and p = 0.041, respectively) after adjusting for age and stage. Individual HER3 and EGFR H-scores were not associated with outcomes in simple or multivariable models. We also found that tumors from chemotherapy-treated TNBC patients with high HER3-EGFR scores exhibited higher immunohistochemical expression of luminal cytokeratins, DNA damage response proteins, and P-cadherin compared with tumors from chemotherapy-treated TNBC patients with low scores (q < 0.25). The top canonical pathway whose components were overexpressed in HER3-EGFR-high TNBCs was Hepatic Fibrosis (p = 0.008), which is linked to distant metastasis, and the top upstream regulator was HNF4A (p = 0.012), a transcription factor for ERBB3 with isoforms that promote liver and gut tumorigenesis. Conclusions: Collectively, our study reveals that HER3-EGFR score may identify chemotherapy-treated TNBC patients at increased risk for distant metastases and death whose tumors may be characterized by fibrotic processes. Our immunohistochemical test thus identifies high-risk TNBCs who may benefit from agents that inhibit HER3-EGFR signaling.

The multifaceted involvement of centrosome amplification (CA) in tumorigenesis is coming into focus following years of meticulous experimentation, which have elucidated the powerful abilities of CA to promote cellular invasion, disrupt stem cell division, drive chromosomal instability (CIN) and perturb tissue architecture, activities that can accelerate tumor progression. Integration of the extant in vitro , in vivo and clinical data suggests that in some tissues CA may be a tumor-initiating event, in others a consequential ‘hit’ in multistep tumorigenesis, and in some others, non-tumorigenic. However, in vivo data are limited and primarily focus on PLK4 (which has CA-independent mechanisms by which it promotes aggressive cellular phenotypes). In vitro breast cancer models suggest that CA can promote tumorigenesis in breast cancer cells in the setting of p53 loss or mutation, which can both trigger CA and promote cellular tolerance to its tendency to slow proliferation and induce aneuploidy. It is thus our perspective that CA is likely an early hit in multistep breast tumorigenesis that may sometimes be lost to preserve aggressive karyotypes acquired through centrosome clustering-mediated CIN, both numerical and structural. We also envision that the robust link between p53 and CA may underlie, to a considerable degree, racial health disparity in breast cancer outcomes. This question is clinically significant because, if it is true, then analysis of centrosomal profiles and administration of centrosome declustering drugs could prove highly efficacious in risk stratifying breast cancers and treating African American (AA) women with breast cancer.

11604 Background: A majority of breast tumors exhibit centrosome amplification (CA), which imparts aggressive phenotypes like chromosomal instability and invasive behavior. Nevertheless, it is unclear whether CA is associated with poor clinical outcomes after adjusting for potentially confounding factors, like stage and age at diagnosis. Methods: We developed a twenty-gene signature, “CA20,” composed of genes related to centrosome structure and/or whose dysregulation induces CA and tested its prognostic value compared with that of CIN25, a chromosomal instability (CIN) signature, in combined multivariable Cox models using the METABRIC and TCGA microarray breast datasets. The n = 1,969 primary breast cancers of the METABRIC dataset were split randomly and approximately equally into training and validation sets, unlike the n = 524 primary invasive breast cancers of the TCGA dataset, which could not be split to preserve power ≈ 0.80, so bootstrapping was instead used. CA20 and CIN25 were dichotomized by average scores and optimal cutpoints based on the log-rank test. Results: In both discovery and validation METRABRIC sets, CA20 was a significant independent predictor of worse breast cancer-specific survival (HR = 2.9, p < 0.001 and 2.4, p < 0.001, respectively, using average scores as cutpoints; similar results obtained using optimal cutpoints) in multivariable Cox models, unlike CIN25. CA20 score was highly correlated with CIN25 score (ρ = 0.93, p < 10-6). In the TCGA dataset, high CA20 score was associated with 3.8- and 3.7-fold worse overall survival (bootstrap-p = 0.001 and 0.002, respectively, for average and optimal cutpoints) after adjusting for tumor stage and age at diagnosis, unlike CIN25. Also in the TCGA dataset, CA20 correlated very strongly with CIN25 (ρ = 0.95, p < 10-6). Finally, using the TCGA dataset, we identified processes and pathways enriched in the CA20-high group (q < 0.05) that may be potential therapeutic targets, such as DNA repair processes, the DNA integrity checkpoint, and regulation of microtubule dynamics. Conclusions: CA20 is a novel signature with robust prognostic value in breast cancer and identifies patients who might respond to centrosome declustering drugs.

Histone deacetylase 6 (HDAC6), a cytoplasmic enzyme important for many biological processes, has recently emerged as a critical regulator of viral infection. HDAC6 exerts this function either directly, via orchestrating various stages of the viral life cycle, or indirectly via modulating cytokine production by host cells. The broad influence of HDAC6 on viral pathogenesis suggests that this protein may represent an antiviral target. However, the feasibility of targeting HDAC6 and the optimal strategy by which this could be accomplished cannot simply be concluded from individual studies. The primary challenge in developing HDAC6-targeted therapies is to understand how its antiviral effect can be selectively harnessed. As a springboard for future investigations, in this review we recapitulate recent findings on the diverse roles of HDAC6 in viral infection and discuss its alluring potential as a novel antiviral target.