Molecular-Genetic Portrait of Breast Cancer with Triple Negative Phenotype.
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ABSTRACT:
SUBMITTER: Ibragimova MK
PROVIDER: S-EPMC8582512 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Triple-negative breast cancer (TNBC) is a high-risk malignancy due to its high capacity for invasion and lack of targeted therapy. Immunotherapy continues to demonstrate efficacy in a variety of cancers, and thus may be a promising strategy for TNBC given the limited therapeutic options currently available for TNBC. In this study, we performed an exhaustive analysis of immunogenic signatures in TNBC based on 2 large-scale breast cancer (BC) genomic data. We compared enrichment levels of 26 immune cell activities and pathways among TNBC, non-TNBC, and normal tissue, and within TNBCs of different genotypic or phenotypic features. We found that almost all analyzed immune activities and pathways had significantly higher enrichment levels in TNBC than non-TNBC. Elevated enrichment of these immune activities and pathways was likely to be associated with better survival prognosis in TNBC. This study demonstrated that TNBC likely exhibits the strongest immunogenicity among BC subtypes, and thus warrants the immunotherapeutic option for TNBC.
| S-EPMC5884188 | biostudies-literature
Project description:Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers. TNBC is associated with early recurrence of disease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes have been associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1 mutation carriers and 16% to 23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancer susceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72 known breast cancer susceptibility loci identified through genome-wide association studies and other large-scale genotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associated with TNBC, but not other forms of breast cancer, suggesting that these are TNBC-specific loci. Thus, TNBC can be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline predisposition alleles. Additional efforts to combine genetic and epidemiologic data are needed to better understand the etiology of this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinical practice through the development of risk prediction models.
| S-EPMC3654815 | biostudies-literature
Project description:Triple-negative breast cancers (TNBCs) are known to be an aggressive group of breast cancers with higher rates of relapse stage for stage compared to ER/PR positive and HER2 positive breast cancers despite optimal loco-regional and systemic therapies. To date, not a single targeted therapy has been approved for the treatment of TNBC, and cytotoxic chemotherapy remains the standard systemic treatment. Recently, gene expression analyses identified six distinct TNBC subtypes, each displaying a unique biology. In this review we will discuss current and upcoming therapeutic strategies exploring novel approaches to targeted treatment of these TNBC subtypes.
| S-EPMC4235783 | biostudies-literature
Project description:IntroductionTriple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs.Materials and methodsThe surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed.ResultsPositive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN-) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P = 0.003 in LN+ cases; P = 0.018 in LN- cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P = 0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival.ConclusionIn TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.
| S-EPMC4231092 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) has been subdivided into six distinct subgroups: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR). We recently identified a subgroup of TNBC with loss of the tumor suppressor PTEN and five specific microRNAs that exhibits exceedingly poor clinical outcome and contains TP53 mutation, RB1 loss and high MYC and WNT signalling. Here, show that these PTEN-low/miRNA-low lesions cluster with BL1 TNBC. These tumors exhibited high RhoA signalling and were significantly stratified on the basis of PTEN-low/RhoA-signalling-high with hazard ratios (HRs) of 8.2 (P?=?0.0009) and 4.87 (P?=?0.033) in training and test cohorts, respectively. For BL2 TNBC, we identified AKT1 copy gain/high mRNA expression as surrogate for poor prognosis (HR?=?3.9; P?=?0.02 and HR?=?6.1; P?=?0.0032). In IM, programmed cell death 1 (PD1) was elevated and predictive of poor prognosis (HR?=?5.3; P?=?0.01 and HR?=?3.5; P?<?0.004). Additional alterations, albeit without prognostic power, characterized each subtype including high E2F2 and TGF? signalling and CXCL8 expression in BL2, high IFN? and IFN? signalling and CTLA4 expression in IM, and high EGFR signalling in MSL, and may be targeted for therapy. This study identified PTEN-low/RhoA-signalling-high, and high AKT1 and PD1 expression as potent prognostications for BL1, BL2 and IM subtypes with survival differences of over 14, 2.75 and 10.5 years, respectively. This intrinsic heterogeneity could be exploited to prioritize patients for precision medicine.
| S-EPMC6911070 | biostudies-literature
Project description:Patients with triple-negative breast cancer (TNBC) lack molecular targets and have an unfavorable outcome. CD155 is overexpressed in human cancers, but whether it plays a role in TNBC is unexplored. Here we found that CD155 was enriched in both TNBC cell lines and tumor tissues. High CD155 expression was related to poor prognosis of breast cancer patients. CD155 was associated with a mesenchymal phenotype. CD155 knockdown induced a mesenchymal-epithelial transition in TNBC cells, and suppressed TNBC cell migration, invasion and metastasis in vitro and in vivo. Mechanistically, CD155 cross-talked with oncogenic IL-6/Stat3 and TGF-?/Smad3 pathways. Moreover, CD155 knockdown inhibited TNBC cell growth and survival. Taken together, these data indicate that CD155 contributes to the aggressive behavior of TNBC; targeting CD155 may be beneficial to these patients.
| S-EPMC7004517 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC), a specific subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2), has clinical features that include high invasiveness, high metastatic potential, proneness to relapse, and poor prognosis. Because TNBC tumors lack ER, PR, and HER2 expression, they are not sensitive to endocrine therapy or HER2 treatment, and standardized TNBC treatment regimens are still lacking. Therefore, development of new TNBC treatment strategies has become an urgent clinical need. By summarizing existing treatment regimens, therapeutic drugs, and their efficacy for different TNBC subtypes and reviewing some new preclinical studies and targeted treatment regimens for TNBC, this paper aims to provide new ideas for TNBC treatment.
| S-EPMC7285581 | biostudies-literature
Project description:Triple negative breast tumours from archived formalin fixed paraffin embeded samples of the National Cancer Institute of Mexico were analyzed for differential gene expressión. Transcriptomic analysis of the 12 tumor samples was done with the FFPE-designed WG-DASL HT assay (Illumina) according to manufacturer’s instructions. This assay measures 29,285 annotated transcripts derived from the RefSeq database corresponding to 20,727 unique genes. Briefly, 200ng of total RNA were reverse-transcribed into biotinylated cDNA, which was then primer-extended with the Assay Specific Oligos. The cDNA was then amplified with universal primers and hybridized to Illumina Human WG DASL HT Expression BeadChip arrays. The Illumina Genome Studio V2010.2 was used to obtain the signal values (AVG-Signal), with no normalization and no background subtraction.The performance of hybridizations was evaluated by assessing the presence of outliers and the noise-to-signal ratios by calculating the ratio of centiles P95/P05 prior to normalisation for each sample. We defined outliers as samples with P95/P05 ratio <9.5. All samples were found to show a correct noise-to-signal ratio (P95/P05>9.6). For differential gene expression analysis, the public dataset GSE32124, which includes 33 fresh frozen tissue samples, generated on the Illumina HumanHT-12 v4.0 beadChip, and which contains 99.98% of the 29,285 probes of the Human WG DASL HT BeadChip was used as normal breast tissue control.
2015-05-12 | E-GEOD-62502 | biostudies-arrayexpress
Project description:Perou's molecular classification defines tumors that neither express hormone receptors nor overexpress HER2 as triple-negative (TN) tumors. These tumors account for approximately 15% of breast cancers. The so-called basaloid tumors are not always synonymous with TN tumors; they differ in the fact that they express different molecular markers, have a higher histologic grade, and have a worse prognosis. Clinically they occur in younger women as interval cancer, and the risk of recurrence is higher within the first 3 years. Distant recurrences in the brain and visceral metastases are more common than in hormone receptor-positive tumors. Therapeutically, despite being highly chemosensitive, their progression-free time is generally short. In terms of chemotherapeutic treatment, anthracyclines and taxanes are useful drugs, and high response rates have been described for the combination of ixabepilone-capecitabine and platinums. The combination with antiangiogenic drugs has also proven useful. A group of new drugs, poly-(ADP-ribose)-polymerase inhibitors, showed favorable results in TN tumors with BRCA mutation. There are currently several ongoing studies with new drugs including epidermal growth factor receptor inhibitors, c-kit inhibitors, Raf/Mek/Map kinase inhibitors and mTOR inhibitors.
| S-EPMC2972557 | biostudies-literature
Project description:PurposeIncreasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR.Experimental designWe obtained pretreatment core-needle biopsies from 105 patients with stage I-III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT.ResultsThe pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage.ConclusionsIn patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.
| S-EPMC8752638 | biostudies-literature