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Purpose The development of multi-gene signatures has led to improvements in identification of breast cancer patients at high risk of recurrence. The prognostic power of commercially available gene signatures is mostly restricted to estrogen receptor (ER)-positive breast cancer. On the contrary, immune-related gene signatures predict prognosis only in ER-negative breast cancer. This study aimed to develop a better prognostic signature for breast cancer. Methods The expressions of long non-coding RNA (lncRNA) genes from 30 independent microarray datasets with a total of 4813 samples were analyzed. A prognostic lncRNA signature was developed based on likelihood-ratio Cox regression analysis. Survival analysis was used to compare the prognostic efficiencies of our signature and 10 previously reported prognostic gene signatures. Results Cox regression analysis on 30 independent datasets showed that the 6-lncRNA signature identified in this study performed as well as five commercially available signatures in recurrence prediction for ER-positive breast cancer. In ER-negative breast cancer, this lncRNA signature was as prognostic as three immune-related gene signatures. Moreover, our lncRNA signature also demonstrated a good capacity to predict recurrence risk for triple-negative breast cancer. Function analysis showed that several lncRNAs in this signature were probably involved in cell proliferation and immune processes. Conclusions A six-LncRNA signature was identified that is prognostic for ER-positive, ER-negative, and triple-negative breast cancers and thus deserves further validation in prospective studies.

Background Aberrant activation of anaplastic lymphoma kinase (ALK) signaling has been found to be involved in the tumorigenesis of multiple types of cancer. The aim of this study was to determine the role of this pathway in the pathogenesis of breast cancer. Methods An ALK pathway signature that we generated previously was used to compute the ALK pathway activity in 6381 breast cancer samples from 42 microarray datasets, and the associations between ALK pathway signature score and clinical variables were examined using logistic regression and survival analyses. Results Our results indicated that high ALK pathway activity was a significant risk factor for hormone receptor‐negative, high‐grade breast cancer in the 42 datasets. ALK pathway activity was positively associated with pathological complete response (pCR) in 15 datasets annotated with patient's neoadjuvant chemotherapy response information (overall odds ratio = 1.67, P < 0.01), and this association was more significant in HER2‐negative and grade 1&2 tumors than in HER2‐positive and grade 3 tumors. ALK pathway activity was also positively associated with recurrence risk in breast cancer patients from 30 datasets annotated with survival information (overall hazard ratio = 1.21, P < 0.01), particularly in patients with age > 50 years old, with positive lymph nodes, or with residual disease after neoadjuvant chemotherapy. Conclusions ALK may be involved in breast cancer tumorigenesis, and ALK pathway signature score may serve as a prognostic biomarker for breast cancer.

Diabetes is directly related to the risk of breast cancer (BC) occurrence and worsened BC prognosis. Currently, there are no specific treatments for diabetes‐associated BC. This paper aims to understand the fundamental mechanisms of diabetes‐induced BC progression and to develop personalized treatments. It reports a metabolic reprogramming strategy (MRS) that pharmaceutical induction of glucose import and glycolysis with metformin and NF‐κB inhibitor (NF‐κBi) while blocking the export of excessive lactate via inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis within the cancer cells. It demonstrates that the MRS shifts the metabolism of BC cells toward higher production of lactate, blocks lactate secretion, prompts intracellular acidification and induces significant cytotoxicity. Moreover, a novel MCT4 inhibitor CB‐2 has been identified by structure‐based virtual screening. A triple combination of metformin, CB‐2, and trabectedin, a drug that impedes NF‐κB signaling, strongly inhibits BC cells. Compared to normal glucose condition, MRS elicits more potent cancer cell‐killing effects under high glucose condition. Animal model studies show that diabetic conditions promote the proliferation and progression of BC xenografts in nude mice and that MRS treatment significantly inhibits HG‐induced BC progression. Therefore, inhibition of MCT4 combined with metformin/NF‐κBi is a promising cancer therapy, especially for diabetes‐associated BC. A metabolic reprogramming strategy (MRS) that pharmaceutical induction of glucose import and glycolysis to even higher levels while blocking the export of excessive lactate leads to a metabolic crisis within the cancer cells. MRS can be realized by pharmacological inhibition of MCT4 combined with metformin/NF‐κBi, which is a promising cancer therapy, especially for diabetes‐associated breast cancer.

Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common in multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction. Semi-quantitative RT-PCR showed frequent OPCML silencing in NPC and other common tumors, with no homozygous deletion detected by multiplex differential DNA-PCR. Instead, promoter methylation of OPCML was frequently detected in multiple carcinoma cell lines (nasopharyngeal, esophageal, lung, gastric, colon, liver, breast, cervix, prostate), lymphoma cell lines (non-Hodgkin and Hodgkin lymphoma, nasal NK/T-cell lymphoma) and primary tumors, but not in any non-tumor cell line and seldom weakly methylated in normal epithelial tissues. Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing. We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated. Ecotopic expression of OPCML led to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells with endogenous silencing. Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies.

Basal-like breast cancer (BLBC) is a type of high-grade invasive breast cancer with high risk of recurrence, metastases, and poor survival. Immune activation in BLBC is a key factor that influences both cancer progression and therapeutic response, although its molecular mechanisms are not well clarified. In this study, we examined five cancer immunity-related pathways (IFNα, IFNγ, STAT3, TGFβ and TNFα) in four large independent breast cancer cohorts ( = 6,381) and their associations with the prognosis of breast cancer subtypes. Activities of the 5 pathways were calculated based on corresponding pathway signatures and associations between pathways and clinical outcomes were examined by survival analysis. Among the five PAM50-based subtypes, BLBC had the highest IFNα, IFNγ, TNFα pathway activities, and the lowest TGFβ activity. The IFNα, IFNγ, TNFα pathway activities were negatively correlated with BLBC recurrence. In contrast, positive association and no association with BLBC recurrence were observed for TGFβ and STAT3 pathways, respectively. TNFα/TGFβ pathway combination improved the prediction of recurrence and chemotherapy response of BLBCs. Immune cell subset analysis in BLBC showed that M0, M1 and M2 macrophage levels were associated with either TNFα or TGFβ pathways, whereas the level of activated memory CD4 T cells were associated with both pathways. Moreover, this T cell subset was most abundant in BLBCs with low TGFβ and high TNFα pathway activities. These results suggested that cooperation of TNFα and TGFβ signaling may be involved in the regulation of memory T cells and anti-cancer immunity in BLBCs. Our data also demonstrate that TNFα/TGFβ pathway combination may represent a better biomarker for BLBC prognosis and clinical management.

The proto-oncogene PIK3CA has been well studied for its activating mutations and genomic amplifications but not single nucleotide polymorphism (SNP) in thyroid cancer. We investigated SNP rs17849071 (minor allele G and major allele T) in PIK3CA in thyroid tumors in 503 subjects by PCR and sequencing of a region of intron 9 carrying this SNP. This SNP was found in both normal and thyroid tumor tissues as well as in different generations of a studied family, confirming it to be a germline genetic event in thyroid tumor patients. In comparison with normal subjects, a dramatically lower prevalence of the heterozygous genotype G/T at rs17849071 was found in patients with follicular thyroid cancer (FTC). Specifically, rs17849071G/T was found in 15% (18/117) normal subjects vs. 1.3% (1/77) FTC patients, with an odds ratio of 0.07 (95% CI 0.01-0.55; P = 0.001). This represents a 93% risk reduction for FTC with this SNP. In contrast, no difference was seen with benign thyroid neoplasms in which the prevalence of rs17849071G/T was 13.1% (17/130), with an odds ratio of 0.83 (95% CI 0.40-1.69; P = 0.72). There was a trend of lower prevalences of rs17849071G/T and odds ratio in other types of thyroid cancer without statistical significance. We also found an interesting inverse relationship of rs17849071G/T with PIK3CA amplification. With copy number ≥4 defined as copy gain, 2.9% (1/34) rs17849071G/T vs. 19.0% (67/352) rs17849071T/T cases displayed PIK3CA amplification (P = 0.01). Conversely, 1.5% (1/68) cases with PIK3CA amplification vs. 10.4% (33/318) cases without PIK3CA amplification harbored rs17849071G/T (P = 0.01). This provides an explanation for the reciprocal relationship of rs17849071G/T with FTC, since PIK3CA amplification is an important oncogenic mechanism in thyroid cancer, particularly FTC. Thus, the present study uncovers an interesting phenomenon that rs17849071G/T is protective against FTC possibly through preventing PIK3CA amplifications.

Both the MAP kinase and PI3K/Akt pathways play an important role in the pathogenesis of melanoma. We conducted the present study to test the hypothesis that targeting the two pathways to potently induce cell inhibition accompanied with thyroid iodide-handling gene expression for adjunct radioiodine ablation could be a novel effective therapeutic strategy for melanoma. We used specific shRNA approaches and inhibitors to individually or dually suppress the MAP kinase and PI3K/Akt pathways and examined the effects on a variety of molecular and cellular responses of melanoma cells that harbored activating genetic alterations in the two pathways. Suppression of the MAP kinase and PI3K/Akt pathways showed potent anti-melanoma cell effects, including the inhibition of cell proliferation, transformation and invasion, induction of G(0)/G(1) cell cycle arrest and, when the two pathways were dually suppressed, cell apoptosis. Remarkably, suppression of the two pathways, particularly simultaneous suppression of them, also induced expression of genes that are normally expressed in the thyroid gland, such as the genes for sodium/iodide symporter and thyroid-stimulating hormone receptor. Melanoma cells were consequently conferred the ability to take up radioiodide. We conclude that dually targeting the MAP kinase and PI3K/Akt pathways for potent cell inhibition coupled with induction of thyroid gene expression for adjunct radioiodine ablation therapy may prove to be a novel and effective therapeutic strategy for melanoma.

Efficient predictive biomarkers are urgently needed to identify non-small cell lung cancer (NSCLC) patients who could benefit from immune checkpoint blockade (ICB) therapy. Since chromatin remodeling is required for DNA repair process, we asked whether mutations in chromatin remodeling genes could increase tumor mutational burden (TMB) and predict response to ICB therapy in NSCLC. Analysis of seven ICB-treated NSCLC cohorts revealed that mutations of three chromatin remodeling-related genes, including KMT2C, BCOR and KDM5C, were significantly associated with ICB response, and combined mutations of these three genes further enhance this association. NSCLC patients with KMT2C/BCOR/KDM5C mutations had comparable clinical outcomes to TMB-high patients in terms of objective response rate, durable clinical benefit and overall survival. Although KMT2C/BCOR/KDM5C mutations were positively correlated with TMB levels in NSCLC, the association of this mutation with better ICB response was independent of tumor TMB and programmed death-ligand 1 (PD-L1) level, and combination of KMT2C/BCOR/KDM5C mutations with TMB or PD-L1 further improve the prediction of ICB response in NSCLC patients. Cancer Genome Atlas (TCGA) pan-cancer analysis suggested that the association of KMT2C/BCOR/KDM5C mutations with ICB response observed here might not result from DNA repair defects. In conclusion, our data indicate that KMT2C/BCOR/KDM5C mutation has the potential to serve as a predictive biomarker, alone or combined with PD-L1 expression or TMB, for ICB therapy in NSCLC.