Differential effects of CD20+ B cells and PD-L1+ immune cells on pathologic complete response and outcome: comparison between inflammatory breast cancer and locally advanced breast cancer patients.

PURPOSE: This study evaluated epidemiologic and immune factors associated with pathologic complete response (pCR), breast cancer-specific survival (BCSS) and disease-free survival (DFS) outcomes in inflammatory (IBC) and locally advanced breast cancer (LABC) patients. METHODS: Tumor-infiltrating lymphocytes (TILs) and CD20+ B-cell frequencies (CD20+), and PD-L1 expression on tumor (PD-L1+carcinoma cells) and immune (PD-L1+TILs) cells were analyzed by immunohistochemistry along with clinicopathologic factors as modifiers of pCR and outcomes in 221 IBC and 162 LABC patients. Analysis included Kaplan-Meier curves and Cox proportional hazard models. RESULTS: IBC and LABC display similar levels of TILs, CD20+, and combined CD20+ and PD-L1+TILs (CD20+PD-L1+TILs), while LABC contained more PD-L1+TILs and PD-L1+ carcinoma cells. Absence of lymphovascular involvement, high TILs, PD-L1+ carcinoma cells, and combined CD20+ and PD-L1+ carcinoma cells correlated with pCR in IBC and LABC patients. High PD-L1+TILs correlated with pCR only in LABC; less lymph node involvement at diagnosis, CD20+ and CD20+PD-L1+TILs correlated with pCR only in IBC (P < 0.04, all comparisons). Achievement of pCR in IBC and LABC patients correlated with BCSS and DFS (P < 0.02). In multivariate analyses, pCR remained an independent prognostic factor of improved DFS in IBC and LABC patients, but of BCSS in only LABC. CD20+PD-L1+TILs remained an independent prognostic factor of improved DFS and BCSS only in IBC. CONCLUSION: CD20+PD-L1+TILs are an independent prognostic biomarker of improved outcomes in IBC, but not LABC. Selecting IBC patients by CD20 and PD-L1 status could stratify patients and potentially identify those in whom activating CD20 agents and anti-PD-1/PD-L1 therapy could be explored.

Adaptive immunity programmes in breast cancer.

The role of the immune system in shaping cancer development and patient prognosis has recently become an area of intense focus in industry and academia. Harnessing the adaptive arm of the immune system for tumour eradication has shown great promise in a variety of tumour types. Differences between tissues, however, necessitate a greater understanding of the adaptive immunity programmes that are active within each tumour type. In breast cancer, adaptive immune programmes play diverse roles depending on the cellular infiltration found in each tumour. Cytotoxic T lymphocytes and T helper type 1 cells can induce tumour eradication, whereas regulatory T cells and T helper type 2 cells are known to be involved in tumour-promoting immunosuppressive responses. Complicating these matters, heterogeneous expression of hormone receptors and growth factors in different tumours leads to disparate, patient-specific adaptive immune responses. Despite this non-conformity in adaptive immune behaviours, encouraging basic and clinical results have been observed that suggest a role for immunotherapeutic approaches in breast cancer. Here, we review the literature pertaining to the adaptive immune response in breast cancer, summarize the primary findings relating to the breast tumour's biology, and discuss potential clinical immunotherapies.

Epigenetic inactivation of TRAIL decoy receptors at 8p12-21.3 commonly deleted region confers sensitivity to Apo2L/trail-Cisplatin combination therapy in cervical cancer.

Multiple chromosomal regions are affected by deletions in cervical cancer (CC) genomes, but their consequence and target gene involvement remains unknown. Our single nucleotide polymorphism (SNP) array identified 8p copy number losses localized to an 8.4 Mb minimal deleted region (MDR) in 36% of CC. The 8p MDR was associated with tumor size, treatment outcome, and with multiple HPV infections. Genetic, epigenetic, and expression analyses of candidate genes at MDR identified promoter hypermethylation and/or inactivation of decoy receptors TNFRSF10C and TNFRSF10D in the majority of CC patients. TNFRSF10C methylation was also detected in precancerous lesions suggesting that this change is an early event in cervical tumorigenesis. We further demonstrate here that CC cell lines exhibiting downregulated expression of TNFRSF10C and/or TNFRSF10D effectively respond to TRAIL-induced apoptosis and this affect was synergistic in combination with DNA damaging chemotherapeutic drugs. We show that the CC cell lines harboring epigenetic inactivation of TRAIL decoy receptors effectively activate downstream caspases suggesting a critical role of inactivation of these genes in efficient execution of extrinsic apoptotic pathway and therapy response. Therefore, these findings shed new light on the role of genetic/epigenetic defects in TRAIL decoy receptor genes in the pathogenesis of CC and provide an opportunity to explore strategies to test decoy receptor gene inactivation as a biomarker of response to Apo2L/TRAIL-combination therapy.

Oxygen regulates molecular mechanisms of cancer progression and metastasis.

Oxygen is the basic molecule which supports life and it truly is "god's gift to life." Despite its immense importance, research on "oxygen biology" has never received the light of the day and has been limited to physiological and biochemical studies. It seems that in modern day biology, oxygen research is summarized in one word "hypoxia." Scientists have focused on hypoxia-induced transcriptomics and molecular-cellular alterations exclusively in disease models. Interestingly, the potential of oxygen to control the basic principles of biology like homeostatic maintenance, transcription, replication, and protein folding among many others, at the molecular level, has been completely ignored. Here, we present a perspective on the crucial role played by oxygen in regulation of basic biological phenomena. Our conclusion highlights the importance of establishing novel research areas like oxygen biology, as there is great potential in this field for basic science discoveries and clinical benefits to the society.

Neoadjuvant Intratumoral Immunotherapy with Cowpea Mosaic Virus Induces Local and Systemic Antitumor Efficacy in Canine Mammary Cancer Patients.

The lack of optimal models to evaluate novel agents is delaying the development of effective immunotherapies against human breast cancer (BC). In this prospective open label study, we applied neoadjuvant intratumoral immunotherapy with empty cowpea mosaic virus-like particles (eCPMV) to 11 companion dogs diagnosed with canine mammary cancer (CMC), a spontaneous tumor resembling human BC. We found that two neoadjuvant intratumoral eCPMV injections resulted in tumor reduction in injected tumors in all patients and in noninjected tumors located in the ipsilateral and contralateral mammary chains of injected dogs. Tumor reduction was independent of clinical stage, tumor size, histopathologic grade, and tumor molecular subtype. RNA-seq-based analysis of injected tumors indicated a decrease in DNA replication activity and an increase in activated dendritic cell infiltration in the tumor microenvironment. Immunohistochemistry analysis demonstrated significant intratumoral increases in neutrophils, T and B lymphocytes, and plasma cells. eCPMV intratumoral immunotherapy demonstrated antitumor efficacy without any adverse effects. This novel immunotherapy has the potential for improving outcomes for human BC patients.

Molecular and epidemiological characteristics of inflammatory breast cancer in Algerian patients.

Inflammatory breast cancer (IBC) shows a high incidence in Tunisia and Egypt but epidemiological and molecular characteristics have not been described in Algeria. We compared 117 IBC and 59 non-IBC locally advanced breast cancers (LABC), for estrogen and progesterone receptors, HER2, and EGFR protein expression by immunohistochemistry, and HER2 gene amplification by chromogenic in situ hybridization. Demographic, clinico-pathological, and molecular variables were compared with chi-square and Fisher's exact tests to test for significance (P < 0.05, two-tailed). Overall survival (OS) and disease-free survival (DFS) were plotted using Kaplan-Meier curves and compared using the log-rank test. Tumor emboli were detected in 77% of IBC. Palpable masses were found in all LABC but only in 32% of IBC (P < 0.001). Recurrences were higher in LABC than in IBC (48 vs. 35%; P = 0.14) but OS was worse in IBC (68 vs. 71%; P = 0.06). There were no significant differences between IBC and LABC by demographics or by clinico-pathological parameters. The majority of IBC and LABC tumors were luminal A (62 and 64%), followed by basal (~18%, each), triple negative (~18%, each), and HER2+ (~10%, each) subtypes. In multivariate analyses, grade was associated with worse OS (P = 0.04), and DFS (P < 0.001) in IBC; chemo- and radio-therapy were associated with improved OS and DFS, respectively (P < 0.05 for each) in LABC. In conclusion, IBC in Algeria shows similar characteristics to IBC described for Egypt and Tunisia with subtle molecular differences. Current therapeutic treatments were not very effective in this population and new approaches are much needed.

Tumor stromal vascular endothelial growth factor A is predictive of poor outcome in inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is a highly angiogenic disease; thus, antiangiogenic therapy should result in a clinical response. However, clinical trials have demonstrated only modest responses, and the reasons for these outcomes remain unknown. Therefore, the purpose of this retrospective study was to determine the prognostic value of protein levels of vascular endothelial growth factor (VEGF-A), one of the main targets of antiangiogenic therapy, and its receptors (VEGF-R1 and -R2) in IBC tumor specimens. PATIENTS AND METHODS: Specimens from IBC and normal breast tissues were obtained from Algerian patients. Tumor epithelial and stromal staining of VEGF-A, VEGF-R1, and VEGF-R2 was evaluated by immunohistochemical analysis in tumors and normal breast tissues; this expression was correlated with clinicopathological variables and breast cancer-specific survival (BCSS) and disease-free survival (DFS) duration. RESULTS: From a set of 117 IBC samples, we evaluated 103 ductal IBC tissues and 25 normal specimens. Significantly lower epithelial VEGF-A immunostaining was found in IBC tumor cells than in normal breast tissues (P <0.01), cytoplasmic VEGF-R1 and nuclear VEGF-R2 levels were slightly higher, and cytoplasmic VEGF-R2 levels were significantly higher (P = 0.04). Sixty-two percent of IBC tumors had high stromal VEGF-A expression. In univariate analysis, stromal VEGF-A levels predicted BCSS and DFS in IBC patients with estrogen receptor-positive (P <0.01 for both), progesterone receptor-positive (P = 0.04 and P = 0.03), HER2+ (P = 0.04 and P = 0.03), and lymph node involvement (P <0.01 for both). Strikingly, in a multivariate analysis, tumor stromal VEGF-A was identified as an independent predictor of poor BCSS (hazard ratio [HR]: 5.0; 95% CI: 2.0-12.3; P <0.01) and DFS (HR: 4.2; 95% CI: 1.7-10.3; P <0.01). CONCLUSIONS: To our knowledge, this is the first study to demonstrate that tumor stromal VEGF-A expression is a valuable prognostic indicator of BCSS and DFS at diagnosis and can therefore be used to stratify IBC patients into low-risk and high-risk groups for death and relapses. High levels of tumor stromal VEGF-A may be useful for identifying IBC patients who will benefit from anti-angiogenic treatment.

A Phase II study of pulse dose imatinib mesylate and weekly paclitaxel in patients aged 70 and over with advanced non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR). METHODS: This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes. RESULTS: Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail. CONCLUSIONS: The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01011075.

Proactive Immunotherapeutic Approaches against Inflammatory Breast Cancer May Improve Patient Outcomes.

Inflammatory breast cancer (IBC) is highly metastatic at the onset of the disease with no IBC-specific treatments, resulting in dismal patient survival. IBC treatment is a clear unmet clinical need. This commentary highlights findings from a recent seminal approach in which pembrolizumab, a checkpoint inhibitor against programmed cell death protein 1 (PD-1), was provided to a triple-negative IBC patient as a neoadjuvant immune therapy combined with anthracycline-taxane-based chemotherapy. We highlight the findings of the case report and offer a perspective on taking a proactive approach to deploy approved immune checkpoint inhibitors. On the basis of our recently published research study, we propose in situ vaccination with direct injection of immunostimulatory agents into the tumor as an option to improve outcomes safely, effectively, and economically for IBC patients.

Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer.

BACKGROUND: Inflammatory mammary cancer (IMC), the counterpart of human inflammatory breast cancer (IBC), is the deadliest form of canine mammary tumors. IMC patients lack specific therapy and have poor outcomes. This proof-of-principle preclinical study evaluated the efficacy, safety, and effect on survival of neoadjuvant intratumoral (in situ) empty cowpea mosaic virus (eCPMV) immunotherapy in companion dogs diagnosed with IMC. METHODS: Ten IMC-bearing dogs were enrolled in the study. Five dogs received medical therapy, and five received weekly neoadjuvant in situ eCPMV immunotherapy (0.2-0.4 mg per injection) and medical therapy after the second eCPMV injection. Efficacy was evaluated by reduction of tumor growth; safety by hematological and biochemistry changes in blood and plasma; and patient outcome by survival analysis. eCPMV-induced immune changes in blood cells were analyzed by flow cytometry; changes in the tumor microenvironment were evaluated by CD3 (T lymphocytes), CD20 (B lymphocytes), FoxP3 (Treg lymphocytes), myeloperoxidase (MPO; neutrophils), Ki-67 (proliferation index, PI; tumor cell proliferation), and Cleaved Caspase-3 (CC-3; apoptosis) immunohistochemistry. RESULTS: Two neoadjuvant in situ eCPMV injections resulted in tumor shrinkage in all patients by day 14 without systemic adverse events. Although surgery for IMC is generally not an option, reduction in tumor size allowed surgery in two IMC patients. In peripheral blood, in situ eCPMV immunotherapy was associated with a significant decrease of Treg+/CD8+ ratio and changes in CD8+Granzyme B+ T cells, which behave as a lagging predictive biomarker. In the TME, higher neutrophilic infiltration and MPO expression, lower tumor Ki-67 PI, increase in CD3+ lymphocytes, decrease in FoxP3+/CD3+ ratio (p<0.04 for all comparisons), and no changes in CC-3+ immunostainings were observed in post-treatment tumor tissues when compared with pretreatment tumor samples. eCPMV-treated IMC patients had a statistically significant (p=0.033) improved overall survival than patients treated with medical therapy. CONCLUSIONS: Neoadjuvant in situ eCPMV immunotherapy demonstrated anti-tumor efficacy and improved survival in IMC patients without systemic adverse effects. eCPMV-induced changes in immune cells point to neutrophils as a driver of immune response. Neoadjuvant in situ eCPMV immunotherapy could be a groundbreaking immunotherapy for canine IMC and a potential future immunotherapy for human IBC patients.

Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance.

Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers.

GPR30 and estrogen receptor expression: new insights into hormone dependence of inflammatory breast cancer.

GPR30 is a novel G protein-coupled estrogen receptor (ER) associated with metastases in breast cancer (BC) and poor survival in endometrial and ovarian tumors. The association of GPR30 expression with inflammatory breast cancer (IBC), an aggressive and commonly hormone-independent form of BC, has not been studied. GPR30, ER, progesterone receptor (PR), epidermal growth factor receptor (EGFR), and HER-2 expression were assessed by immunohistochemistry (and FISH for HER-2) in 88 primary IBCs. GPR30 expression was correlated with patient overall survival (OS), disease-free survival (DFS), pathologic variables, and other biomarkers. GPR30 expression was found in 69% of IBC cases. ER, PR, HER-2, and EGFR were found in 43, 35, 39, and 34% of IBC cases, respectively. GPR30 expression correlated inversely with ER expression (P = 0.02). Co-expression of ER and GPR30 was found in 24% of IBC samples; 19% expressed only ER and 46% expressed only GPR30. Univariate analysis showed no association between GPR30 expression and OS or DFS. However, co-expression of ER and GPR30 was associated with improved OS (P < 0.03) and marginally with DFS (P < 0.06); the absence of both ER and GPR30 was associated with worse OS and DFS (P = 0.03 for both). Multivariate analysis identified ER as an independent prognostic factor of OS (P = 0.008) and DFS (P = 0.02). The majority of IBC tumors are GPR30-positive, suggesting that estrogen signaling may be active in ER-negative IBC patients. These findings suggest potential new therapeutic targets for IBC such as novel endocrine agents or direct modulation of GPR30.

Co-expression of GPR30 and ERbeta and their association with disease progression in uterine carcinosarcoma.

OBJECTIVE: We sought to evaluate the expression of G protein-coupled receptor 30 (GPR30) and estrogen receptor (ER)beta in uterine carcinosarcoma (CS). STUDY DESIGN: Immunohistochemistry was performed using antibodies to GPR30, ERbeta, ERalpha, and progesterone receptor (PR). The staining intensity and percentage of positive cells were scored for each tissue section. Expression levels were compared using the Wilcoxon rank sum test. Correlation was evaluated by Spearman rho and logistic regression. RESULTS: Compared with normal endometrium, CS had lower ERalpha and PR expression (both P < .01) but higher GPR30 epithelial expression (P = .03). Advanced-stage CS had higher GPR30 (P < .01) and ERbeta (P = .02) epithelial expression compared with early-stage CS. Expression of GPR30 and ERbeta correlated with each other (P < .01), and not with ERalpha or PR. CONCLUSION: In uterine CS, GPR30 and ERbeta are coordinately overexpressed and expression levels increase in advanced-stage disease, supporting the involvement of alternative ERs in disease progression.

Protocadherin PCDH10, involved in tumor progression, is a frequent and early target of promoter hypermethylation in cervical cancer.

Cervical cancer (CC) is the second most common cancer in women. Currently, no tractable molecular-based therapeutic targets exist for patients with invasive CC and no predictive markers of risk assessment for progression of precancerous lesions are identified. New molecular insights into CC pathogenesis are urgently needed. Towards this goal, we first determined the copy number alterations of chromosome 4 and then examined the role of PCDH10 mapped to 4q28 as a candidate tumor suppressor gene. We identified monosomy 4 in 47% of 81 invasive CC studied by SNP array and found that 91% of 130 invasive CC harboring methylation in the promoter region of the PCDH10 gene. We then showed that aberrant promoter hypermethylation of PCDH10 is associated with downregulation of gene expression and cell lines exposed to demethylating agent resulted in profound reactivated gene expression. We also showed that the promoter methylation in the PCDH10 gene occurs at an earliest identifiable stage of low-grade squamous intraepithelial lesion. Our studies demonstrate that inactivation of PCDH10 may be a critical event in CC progression and form a potentially useful therapeutic target for CC.

GPR30 predicts poor survival for ovarian cancer.

OBJECTIVES: GPR30 is a 7-transmembrane G protein-coupled estrogen receptor that functions alongside traditional estrogen receptors to regulate cellular responses to estrogen. Recent studies suggest that GPR30 expression is linked to lower survival rates in endometrial and breast cancer. This study was conducted to evaluate GPR30 expression in ovarian tumors. METHODS: GPR30 expression was analyzed using immunohistochemistry and archival specimens from 45 patients with ovarian tumors of low malignant potential (LMP) and 89 patients with epithelial ovarian cancer (EOC). Expression, defined as above or below the median (intensity times the percentage of positive epithelial cells) was correlated with predictors of adverse outcome and survival. RESULTS: GPR30 expression above the median was observed more frequently in EOC than in LMP tumors (48.3% vs. 20%, p=0.002), and in EOC was associated with lower 5-year survival rates (44.2% vs. 82.6%, Log-rank p<0.001). Tumor grade and FIGO stage, the other significant predictors of survival, were used to stratify cases into "high risk" and "low risk" groups. The 5-year survival rate for "low risk" EOC (all grade 1 and Stage I/II, grade 2) was 100%. In "high risk" EOC (all grade 3 and Stage III/IV, grade 2), the difference in 5-year survival by GPR 30 expression was significant (33.3% vs. 72.4%, p=0.001). CONCLUSIONS: The novel estrogen-responsive receptor GPR30 is preferentially expressed in "high risk" EOC and is associated with lower survival rates. Further investigation of GPR30 as a potential target for therapeutic intervention in high risk EOC is warranted.

Estrogen and progesterone receptor status and outcome in epithelial ovarian cancers and low malignant potential tumors.

OBJECTIVE: Receptors for estrogen (ER) and progesterone (PR) are prognostic indicators for a variety of endocrine tumors including breast and endometrial. This study was conducted to determine if ER and PR expression patterns are predictive of outcome in patients with epithelial ovarian cancer (EOC) or ovarian low malignant potential (LMP) tumors. METHODS: ER and PR protein levels were assessed by immunohistochemistry in 45 LMP and 89 EOC samples. Patterns of ER/PR expression (individually and combinations of ER-/PR-, ER+/PR-, ER-/PR+, and ER+/PR+) were correlated with standard prognostic factors of overall survival (OS) in this patient population. RESULTS: For patients with EOC, the 5-year OS per ER-/PR+, ER+/PR-, ER+/PR+, and ER-/PR- expression was 83%, 79%, 61%, and 48%, respectively, and these differences were statistically significant. In multivariate analyses, ER/PR expression patterns were found to be independent predictors of OS, as were the classical prognostic factors of grade, stage, debulking, and chemotherapy response to treatment. In patients with mucinous LMP tumors, ER and PR were absent. Because no LMP patients died of disease during the studied period, no correlation analysis with OS could be performed. CONCLUSIONS: Patterns of ER/PR expression provide prognostic information in EOC. Additional studies evaluating hormonal inhibition may help personalize the therapy of patients with ovarian cancer.

Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression.

Recurrent karyotypic abnormalities are a characteristic feature of cervical cancer (CC) cells, which may result in deregulated expression of important genes that contribute to tumor initiation and progression. To examine the role of gain of the long arm of chromosome 20 (20q), one of the common chromosomal gains in CC, we evaluated CC at various stages of progression using single nucleotide polymorphism (SNP) array, gene expression profiling, and fluorescence in situ hybridization (FISH) analyses. This analysis revealed copy number increase (CNI) of 20q in >50% of invasive CC and identified two focal amplicons at 20q11.2 and 20q13.13 in a subset of tumors. We further demonstrate that the acquisition of 20q gain occurs at an early stage in CC development and the high-grade squamous intraepithelial lesions (HSIL) that exhibit 20q CNI are associated (P = 0.05) with persistence or progression to invasive cancer. We identified a total of 26 overexpressed genes as consequence of 20q gain (N = 14), as targets of amplicon 1 (N = 9; two genes also commonly expressed with 20q gain) and amplicon 2 (N = 6; one gene also commonly expressed with 20q gain). These include a number of functionally important genes in cell cycle regulation (E2F1, TPX2, KIF3B, PIGT, and B4GALT5), nuclear function (CSEL1), viral replication (PSMA7 and LAMA5), methylation and chromatin remodeling (ASXL1, AHCY, and C20orf20), and transcription regulation (TCEA2). Our findings implicate a role for these genes in CC tumorigenesis, represent an important step toward the development of clinically significant biomarkers, and form a framework for testing as molecular therapeutic targets.

Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha.

BACKGROUND: Copy number gains and amplifications are characteristic feature of cervical cancer (CC) genomes for which the underlying mechanisms are unclear. These changes may possess oncogenic properties by deregulating tumor-related genes. Gain of short arm of chromosome 5 (5p) is the most frequent karyotypic change in CC. METHODS: To examine the role of 5p gain, we performed a combination of single nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and gene expression analyses on invasive cancer and in various stages of CC progression. RESULTS: The SNP and FISH analyses revealed copy number increase (CNI) of 5p in 63% of invasive CC, which arises at later stages of precancerous lesions in CC development. We integrated chromosome 5 genomic copy number and gene expression data to identify key target over expressed genes as a consequence of 5p gain. One of the candidates identified was Drosha (RNASEN), a gene that is required in the first step of microRNA (miRNA) processing in the nucleus. Other 5p genes identified as targets of CNI play a role in DNA repair and cell cycle regulation (BASP1, TARS, PAIP1, BRD9, RAD1, SKP2, and POLS), signal transduction (OSMR), and mitochondrial oxidative phosphorylation (NNT, SDHA, and NDUFS6), suggesting that disruption of pathways involving these genes may contribute to CC progression. CONCLUSION: Taken together, we demonstrate the power of integrating genomics data with expression data in deciphering tumor-related targets of CNI. Identification of 5p gene targets in CC denotes an important step towards biomarker development and forms a framework for testing as molecular therapeutic targets.

Comparative aspects of canine and human inflammatory breast cancer.

Inflammatory breast cancer (IBC) in humans is the most aggressive form of mammary gland cancer and shares clinical, pathologic, and molecular patterns of disease with canine inflammatory mammary carcinoma (CIMC). Despite the use of multimodal therapeutic approaches, including targeted therapies, the prognosis for IBC/CIMC remains poor. The aim of this review is to critically analyze IBC and CIMC in terms of biology and clinical features. While rodent cancer models have formed the basis of our understanding of cancer biology, the translation of this knowledge into improved outcomes has been limited. However, it is possible that a comparative "one health" approach to research, using a natural canine model of the disease, may help advance our knowledge on the biology of the disease. This will translate into better clinical outcomes for both species. We propose that CIMC has the potential to be a useful model for developing and testing novel therapies for IBC. Further, this strategy could significantly improve and accelerate the design and establishment of new clinical trials to identify novel and improved therapies for this devastating disease in a more predictable way.