Xin-Xia Tian

Hormone receptor (HR)–positive breast cancer accounts for approximately 60% of all breast cancer cases, for which endocrine therapy represents the mainstay of treatment; however, the development of therapeutic resistance substantially limits its clinical efficacy. Extracellular adenosine 5′-triphosphate (ATP) has been implicated as a key mediator of metastasis and chemotherapy resistance in multiple malignancies, including breast cancer, yet its role in endocrine resistance remains poorly defined. Here, we demonstrate that extracellular ATP upregulates glycogen phosphorylase L (PYGL) expression in ER-positive breast cancer cells following endocrine treatment, thereby promoting endocrine resistance. Mechanistically, extracellular ATP activates the P2Y12–AhR signaling axis, leading to increased PYGL expression, enhanced glycolytic activity, and subsequent resistance to endocrine therapy. Moreover, elevated PYGL expression was strongly associated with reduced endocrine therapy sensitivity in breast cancer organoids and clinical tumor specimens. Collectively, these findings identify extracellular ATP–driven PYGL activation as a critical mechanism underlying endocrine resistance and suggest that targeting this pathway may represent a promising strategy to improve endocrine therapy efficacy in breast cancer patients.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that there appeared to be two instances of overlapping data panels comparing between the cell migration and invasion assay data shown in Figs. 4 and 6 on p. 143 and 145, respectively, such that data which were intended to represent the results from differently performed experiments had apparently been derived from the same original sources. In addition, the authors themselves realized that incorrect western blotting data for Snail protein in Fig. 10A on p. 147 had been included in the figure. The authors were able to re‑examine their original data files, and realized that the affected data panels in these figures had inadvertently been incorporated into them incorrectly. The revised versions of Figs. 4, 6, and 10, featuring the correct data for the 'NC / Control' panels in Fig. 4B and C and the 'siRNA2 / ATP 12 h' panels in Fig. 4A and B, a replacement data panel for the 'siRNA1 / Control' experiment in Fig. 6, and the correct western blotting data for Snail protein in Fig. 10A (together with a revised histogram for the MCF7 cell line relating to Fig. 10A) are shown on the next three pages. The authors wish to emphasize that the errors made in compiling these figures did not affect the overall conclusions reported in the paper, and they are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this corrigendum. All the authors agree to the publication of this corrigendum, and also apologize to the readership for any inconvenience caused. [Oncology Reports 39: 138‑150, 2018; DOI: 10.3892/or.2017.6081].

Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) accounts for about 25% of all subgroups of MB. Tumor microenvironment (TME) may play a key role in the tumor progression and therapeutic resistance. Tumor‐associated astrocytes (TAAs) are reshaped to drive tumor progression through multiple paracrine signals. However, the mechanism by which TAAs modulate MB cells remains elusive. Here, we illuminated that TAAs showed a specific and dynamic pattern during SHH‐MB development. Most TAAs gathered to the tumor margin during the tumor progression, rather than evenly distributed in the early‐stage tumors. We further demonstrated that lipocalin‐2 (LCN2) secreted by TAAs could promote the tumor growth and was correlated with the poor prognosis of MB patients. Knocking down LCN2 in TAAs in vitro impeded the proliferation and migration abilities of MB cells. In addition, we identified that TAAs accelerated the tumor growth by secreting LCN2 via STAT3 signaling pathway. Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 and AAV‐Lcn2 shRNA, respectively, in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo. In summary, we for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH‐MB and provided a potential therapeutic strategy targeting TAAs.

Most genome-wide association study (GWAS)–identified breast cancer–associated causal variants remain uncharacterized. To provide a framework of understanding GWAS-identified variants to function, we performed a comprehensive study of noncoding regulatory variants at theNTN4locus (12q22) andNTN4gene in breast cancer etiology. We find that rs11836367 is the more likely causal variant, disrupting enhancer activity in both enhancer reporter assays and endogenous genome editing experiments. The protective T allele of rs11837367 increases the binding of GATA3 to the distal enhancer and up-regulatesNTN4expression. In addition, we demonstrate that loss ofNTN4gene in mice leads to tumor earlier onset, progression, and metastasis. We discover thatNTN4, as a tumor suppressor, can attenuate the Wnt signaling pathway by directly binding to Wnt ligands. Our findings bridge the gaps among breast cancer–associated single-nucleotide polymorphisms, transcriptional regulation ofNTN4, and breast cancer biology, which provides previously unidentified insights into breast cancer prediction and prevention.

Our previous works have indicated that extracellular ATP is an important prometastasis factor. However, the molecular mechanism involved needs to be further studied. We demonstrated that extracellular ATP treatment could upregulate the expression of connective tissue growth factor (CTGF) in both triple‐negative breast cancer (TNBC) cells and endothelial cells (ECs). Extracellular ATP stimulated the migration of TNBC cells and ECs, and angiogenesis of ECs via the P2Y2––YAP‐CTGF axis. Furthermore, we demonstrated that adenosine triphosphate (ATP) stimulated TNBC cell adhesion to ECs and transmigration through the EC layer via CTGF by upregulation of integrin β1 on TNBC cells and VCAM‐1 on ECs. Both apyrase (ATP‐diphosphohydrolase) and CTGF shRNA treatments could inhibit the metastasis of inoculated tumors to lung and liver in a mouse model, and these treated tumors had fewer blood vessels. Collectively, our data indicated that extracellular ATP promotes tumor angiogenesis and the interactions between TNBC cells and ECs through upregulation of CTGF, thereby stimulating TNBC metastasis. The pleiotropic effects of ATP in angiogenesis and cell adhesion suggest that extracellular ATP or CTGF could be an effective target for TNBC therapy.

We have previously demonstrated that extracellular adenosine 5'-triphosphate (ATP) promotes breast cancer cell chemoresistance. However, the underlying mechanism remains unclear. Using a cDNA microarray, we demonstrated that extracellular ATP can stimulate hypoxia-inducible factor (HIF) signaling. In this study, we report that hypoxia-inducible factor 1α (HIF-1α) was upregulated after ATP treatment and mediated the ATP-driven chemoresistance process. We aimed to investigate the mechanisms and identify potential clinically relevant targets that are involved. Using mass spectrometry, we found that aldolase A (ALDOA) interacts with HIF-1α and increases HIF-1α expression. We then demonstrated that STAT3-ALDOA mediates ATP-HIF-1α signaling and upregulates the HIF-1 target genes adrenomedullin (ADM) and phosphoinositide-dependent kinase-1 (PDK1). Moreover, we show that PI3K/AKT acts upstream of HIF-1α in ATP signaling and contributes to chemoresistance in breast cancer cells. In addition, HIF-1α-knockdown or treatment with direct HIF inhibitors combined with the ATP hydrolase apyrase in MDA-MB-231 cells induced enhanced drug sensitivity in nude BALB/c mice. We then used in vitro spheroid formation assays to demonstrate the significance of ATP-HIF-1α in mediating chemoresistance. Furthermore, considering that indirect HIF inhibitors are effective in clinical cancer therapy, we treated tumor-bearing BALB/c mice with STAT3 and PI3K/AKT inhibitors and found that the dual-targeting strategy sensitized breast cancer to cisplatin. Finally, using breast cancer tissue microarrays, we found that ATP-HIF-1α signaling is associated with cancer progression, poor prognosis, and resistance to chemotherapy. Taken together, we suggest that HIF-1α signaling is vital in ATP-driven chemoresistance and may serve as a potential target for breast cancer therapies.

Segmentation of pathological images is essential for accurate disease diagnosis. The quality of manual labels plays a critical role in segmentation accuracy; yet, in practice, the labels between pathologists could be inconsistent, thus confusing the training process. In this work, we propose a novel label re-weighting framework to account for the reliability of different experts' labels on each pixel according to its surrounding features. We further devise a new attention heatmap, which takes roughness as prior knowledge to guide the model to focus on important regions. Our approach is evaluated on the public Gleason 2019 datasets. The results show that our approach effectively improves the model's robustness against noisy labels and outperforms state-of-the-art approaches.

Purpose This study aimed to investigate whether genetic polymorphisms in TGFB1 contribute to breast cancer (BC) susceptibility, and explore the mechanism of action. Methods A total of 7 tagging SNPs (tSNPs) were genotyped in 1161 BC cases and 1337 age-matched controls among Chinese Han population. Bioinformatics analysis was used to predict functional SNP closely linked to tSNPs. Luciferase gene reporter assay was performed to determine the effect of genetic variants on promoter activity. DNA pull-down assay and mass spectrometry were used to identify the differentially binding proteins to genetic variants. Results Genotyping analysis showed that rs1800469 (C>T) in the 5′ regulatory region of TGFB1 was associated with reduced BC risk. Bioinformatics analysis predicted that rs11466313 (-2389_-2391 Del/AGG) in the 5′ regulatory region of TGFB1, was closely linked to tSNP rs1800469 and could be functional. The genotyping of rs11466313 by PCR-SSCP showed that rs11466313 also conferred decreased BC risk. Luciferase assays demonstrated that rs11466313 minor allele reduced over ninefold of promoter activity compared with its major allele (p < 0.001). DNA pull-down assay and mass spectrometry revealed that rs11466313 minor allele lost the binding ability with FAM98B and HSP90B. Knocking down FAM98B but not HSP90B, the enhanced promoter activity driven by TGFB1 rs11466313 major allele was attenuated. Conclusions This study elucidates the impact of functional polymorphism rs11466313 in the regulatory region of TGFB1 on breast cancer susceptibility and gene expression, and could be helpful for future research to determine the value of this TGFB1 variant in the clinical setting.

Slug, a member of the Snail family of transcriptional repressors, plays a key role in cancer progression, cellular plasticity, and epithelial to mesenchymal transition (EMT). Slug is a fast-turnover protein and its stability is controlled by post-translational modifications. Here, we identified that Slug is acetylated by acetyltransferase CREB-binding protein (CBP) in breast cancer cells. CBP directly interacts with the C-terminal domain of Slug through its catalytic histone acetyltransferase (HAT) domain, leading to acetylation of Slug at lysines 166 and 211. Analysis with acetylation-specific antibodies revealed that Slug is highly acetylated in metastatic breast cancer cells. Notably, Slug acetylation, mediated by CBP at lysines 166 and 211, doubles its half-life and increases its stability. Further, acetylated Slug downregulates the expression of E-cadherin, the epithelial marker, and upregulates the expression of N-cadherin and vimentin, thereby promoting breast cancer cell migration. In conclusion, the present study demonstrates that CBP-mediated Slug acetylation increases its stability, promoting EMT and migration of breast cancer cells.

Our previous research demonstrated that extracellular adenosine 5′-triphosphate (ATP) could promote breast cancer cell invasion. However, the impact of extracellular ATP on chemoresistance and the mechanisms behind ATP pro-invasion and pro-chemoresistance remain unclear. Here we aimed to determine the molecules or signaling pathways involved. cDNA microarray was performed to identify the differentially expressed genes before and after ATP treatment. As a result, Sex-determining region Y-box 9 (SOX9) was up-regulated after ATP treatment in breast cancer cells. In vitro invasion and migration assays demonstrated that knocking down SOX9 attenuated ATP-driven invasive capability. Mass spectrometry and co-IP revealed that SOX9 interacted with Janus kinase 1 (JAK1). Afterward, IL-6-JAK1-STAT3 signaling was demonstrated to promote SOX9 expression and invasion following ATP treatment. Notably, ATP-IL-6-SOX9 signaling was shown to stimulate chemoresistance in breast cancer cells. ChIP assays identified some potential SOX9 target genes, among which carcinoembryonic antigen-related cell adhesion molecule 5/6 (CEACAM5/6) was demonstrated to mediate ATP pro-invasive function, while ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) mediated ATP-driven chemoresistance. In addition, SOX9-knockdown and apyrase (an ATP hydrolase)-treated MDA-MB-231 cells illustrated decreased tumor growth and enhanced drug sensitivity in nude mice. In vitro spheroid formation assays also proved the significance of ATP-SOX9 in mediating chemoresistance. Moreover, molecules involved in ATP-SOX9 signaling were up-regulated in human breast carcinoma specimens and were associated with poor prognosis. Altogether, SOX9 signaling is vital in ATP-driven invasion and chemoresistance, which may serve as a potential target for breast cancer therapies.