Biological differences between normal and cancer-associated fibroblasts in breast cancer.

Background: Cancer-associated fibroblasts (CAFs) constitute the primary constituents of the tumor microenvironment (TME) and exert significant influences on cancer progression. However, adequate comprehension of CAF profiles in breast cancer, as well as the precise mechanisms underlying their promotion of cancer, remains lacking. Objectives: To discerns the biological differences between normal fibroblasts (NFs) and CAFs in breast cancer and explore the underlying mechanism. Methods: Three pairs of CAFs and NFs were isolated from breast cancer patients of diverse subtypes who had not undergone prior radiotherapy or chemotherapy. Morphological characteristics of CAFs and NFs were assessed through optical and electron microscopy, their biological attributes were examined using cell counting kits and transwell assays, and their impact on breast cancer cells was simulated using a coculture system. Furthermore, the miRNA profiles of CAFs and NFs were sequenced via an Illumina HiSeq 2500 platform. Results: CAFs exhibited higher growth rate and motility than NFs and a stronger potential to promote the malignancy of breast cancer cells. RNA sequencing of both NFs and CAFs revealed differentially expressed miRNAs with notable variability among distinct patients within their NFs and CAFs, while the enrichment of the target genes of differentially expressed miRNAs within both GO terms and KEGG pathways demonstrated significant similarity across patients with different profiles. Conclusion: CAFs have greater malignancy and higher potential to influence the growth, migration, invasion and chemoresistance of cocultured breast cancer cells than NFs. In addition, the miRNAs that are differentially expressed in CAFs when compared to NFs display substantial variability across patients with distinct breast cancer subtypes, while the enrichment of target genes regulated by these miRNAs, within GO terms and KEGG pathways, remains remarkably consistent among patients with varying profiles.

Cancer-associated fibroblasts in breast cancer: Challenges and opportunities.

The tumor microenvironment is proposed to contribute substantially to the progression of cancers, including breast cancer. Cancer-associated fibroblasts (CAFs) are the most abundant components of the tumor microenvironment. Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors, generating exosomes, releasing nutrients, reshaping the extracellular matrix, and suppressing the function of immune cells. CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers. Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials. Here, we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer. We hope that summarizing CAF-related studies from a historical perspective will help to accelerate the development of CAF-targeted therapeutic strategies for breast cancer.

Corrigendum: STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1.

[This corrects the article DOI: 10.3389/fonc.2021.697950.].

STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1.

Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance in vivo. Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.

Establishment and Characterization of a HER2-Positive Cell Line Derived From the Pleural Effusion of a Drug-Resistant Breast Cancer Patient.

Drug resistance is a daunting challenge in the treatment of breast cancer, making it an urgent problem to solve in studies. Cell lines are important tools in basic and preclinical studies; however, few breast cell lines from drug-resistant patients are available. Herein, we established a novel HER2-positive breast cancer cell line from the pleural effusion of a drug-resistant metastatic breast cancer patient. This cell line has potent proliferative capability and tumorigenicity in nude mice but weak invasive and colony-forming capability. The molecular subtype of the cell line and its sensitivity to chemotherapeutics and HER2-targeting agents are different from those of its origin, suggesting that the phenotype changes between the primary and metastatic forms of breast cancer.

PLAC8 promotes adriamycin resistance via blocking autophagy in breast cancer.

Adriamycin (ADM) is currently one of the most effective chemotherapeutic agents in breast cancer treatment. However, growing resistance to ADM could lead to treatment failure and poor outcome. PLAC8 was reported as a novel highly conserved protein and functioned as an oncogene or tumour suppressor in various tumours. Here, we found higher PLAC8 expression was correlated with worse outcome and aggressive phenotype in breast cancer. Breast cancer patients with higher PLAC8 expression showed potential ADM resistance. In vitro experiments further confirmed that PLAC8 inhibited by siRNA or enforced overexpression by infecting pcDNA3.1(C)-PLAC8 plasmid correspondingly decreased or increased ADM resistance. Subsequently, we demonstrated that ectopic PLAC8 expression in MCF-7/ADMR cell blocked the accumulation of the autophagy-associated protein LC3 and resulted in cellular accumulation of p62. Rapamycin-triggered autophagy significantly increased cell response to ADM, while the autophagy inhibitor 3-MA enhanced ADM resistance. 3-MA and PLAC8 could synergistically cause ADM resistance via blocking the autophagy process. Additionally, the down-regulation of p62 by siRNA attenuated the activation of autophagy and PLAC8 expression in breast cancer cells. Thus, our findings suggest that PLAC8, through the participation of p62, inhibits autophagy and consequently results in ADM resistance in breast cancer. PLAC8/p62 pathway may act as novel therapeutic targets in breast cancer treatment and has potential clinical application in overcoming ADM resistance.

LncRNA SLC16A1-AS1 is upregulated in hepatocellular carcinoma and predicts poor survival.

BACKGROUND: Long non-coding RNAs (LncRNAs) are broadly transcribed in the genome of human and animals, they play critical roles in cellular process, and participate in the progression of multiple diseases, including cancer. SLC16A1-AS1 is a tumor suppressive lncRNA in lung cancer. This study aimed to investigate the involvement of lncRNA SLC16A1-AS1 in hepatocellular carcinoma (HCC). METHOD: A total of 64 HCC patients were subjected to biopsy to obtain paired HCC and non-tumor tissues. Expression of SLC16A1-AS1 and miR-141 in paired tissues was determined by RT-qPCR. Correlations were analyzed by linear regression. Overexpression of SLC16A1-AS1 and miR-141 were achieved in HCC cells to explore the interactions between them. The methylation of the gene encoding miR-141 in HCC cells was detected by methylation-specific PCR (MSP). CCK-8 assay was performed for cell proliferation assay. RESULTS: SLC16A1-AS1 was upregulated in HCC and its high expression levels predicted poor survival of HCC patients. Expression levels of miR-141 were lower in HCC patients and were inversely correlated with the expression levels of SLC16A1-AS1. In HCC cells, overexpression of SLC16A1-AS1 led to downregulation of miR-141, while overexpression of miR-141 did not regulate the expression of SLC16A1-AS1. In addition, overexpression of SLC16A1-AS1 led to increased methylation of miR-141. And overexpression of SLC16A1-AS1 attenuated the inhibitory effects of miR-141 on HCC cell proliferation. CONCLUSION: SLC16A1-AS1 is upregulated in HCC and predicts poor survival. In addition, SLC16A1-AS1 may downregulate miR-141 through methylation to promote cancer cell proliferation.

[Retracted] LINC01638 silencing inhibits cancer cell proliferation in colorectal adenocarcinoma through interaction with RUNX2.

Following the publication of the above paper, the authors drew to the Editor's attention that they had identified some errors in Fig. 5A. First, the authors were unable to locate the original images for Fig. 5A; furthermore, repetitions of the same experiments yielded results that were opposite to those that the authors had originally reported. These results were integral to the study, and affected the reported conclusions in the article. Therefore, the authors requested that the paper be withdrawn from the publication. The Editor of Molecular Medicine Reports has considered the authors' request, and agrees that the article should be retracted from the Journal. Note that all that authors agree with the retraction of this paper, and the Editor and the authors apologize to the readership of the Journal for any inconvenience caused. [the original article was published in Molecular Medicine Reports 19: 5275-5280, 2019; DOI: 10.3892/mmr.2019.10191].

Regulation of tamoxifen sensitivity by the PLAC8/MAPK pathway axis is antagonized by curcumin-induced protein stability change.

Tamoxifen resistance remains the major obstacle to the estrogen receptor positive breast cancer endocrine therapy. Placenta-specific 8 (PLAC8) has been implicated in epithelial-mesenchymal transition and tumorigenesis. However, the molecular mechanisms underlying PLAC8 function in the context of tamoxifen resistance are unclear. Curcumin has attracted considerable attention in the last decades. It is isolated from Curcuma longa and has beneficial effects in cancer therapy. We studied this property by using MCF-7 and tamoxifen-resistant breast cancer cells (MCF-7/TAM) cell lines. PLAC8 can regulate MCF-7/TAM cell drug sensitivity through the MAPK/ERK pathway and shows the potential effects of curcumin or as a possible druggable target against tamoxifen failure.

Targeting ferroptosis in breast cancer.

Ferroptosis is a recently discovered distinct type of regulated cell death caused by the accumulation of lipid-based ROS. Metabolism and expression of specific genes affect the occurrence of ferroptosis, making it a promising therapeutic target to manage cancer. Here, we describe the current status of ferroptosis studies in breast cancer and trace the key regulators of ferroptosis back to previous studies. We also compare ferroptosis to common regulated cell death patterns and discuss the sensitivity to ferroptosis in different subtypes of breast cancer. We propose that viewing ferroptosis-related studies from a historical angle will accelerate the development of ferroptosis-based biomarkers and therapeutic strategies in breast cancer.

LINC01638 silencing inhibits cancer cell proliferation in colorectal adenocarcinoma through interaction with RUNX2.

lncRNA LINC01638 has been revealed to play an oncogenic role in triple negative breast cancer. The present study was carried out to investigate the involvement of LINC01638 in colorectal adenocarcinoma. In the present study it was observed that LINC01638 in plasma was upregulated in colorectal adenocarcinoma patients compared to healthy controls. Plasma levels of LINC01638 were affected by tumor size but not by distant metastasis. Plasma levels of Runt­related transcription factor 2 (RUNX2) were also higher in colorectal adenocarcinoma patients than in healthy controls, and were positively correlated with plasma levels of LINC01638 in colorectal adenocarcinoma patients but not in healthy controls. ROC curve analysis revealed that upregulation of LINC01638 distinguished colorectal adenocarcinoma at stage I and II from healthy controls. LINC01638 shRNA knockdown led to RUNX2 downregulation, while RUNX2 overexpression exhibited no significant effects on LINC01638. LINC01638 shRNA knockdown inhibited and RUNX2 overexpression promoted the proliferation of colorectal adenocarcinoma cells. RUNX2 overexpression attenuated the effects of LINC01638 shRNA knockdown on cancer cell proliferation. Therefore, lncRNA LINC01638 silencing may inhibit cancer cell proliferation in colorectal adenocarcinoma through its interaction with RUNX2.

MiR-488 suppresses cell proliferation and invasion by targeting ADAM9 and lncRNA HULC in hepatocellular carcinoma.

MicroRNAs (miRNAs) have been identified as regulators of tumor proliferation, invasion, and metastasis in hepatocellular carcinoma (HCC). In the current study, we determined the clinical significance and biological role of miR-488 in HCC. Our results demonstrated that the expression of miR-488 was notably downregulated in HCC tissues compared with paired adjacent normal tissues. Lower miR-488 expression was positively associated with tumor size, vascular invasion, and shorter overall survival (OS) in HCC patients. Furthermore, gain-and-lost function assays showed that upregulation of miR-488 significantly inhibited cell proliferation, colony formation, cell invasion, and the epithelial-to-mesenchymal transition (EMT) process. We showed that ADAM9 served as a direct target for miR-488 and mediated lower miR-488 expression, thus inducing cell proliferation and invasion in HCC. Moreover, we found that lncRNA HULC is a target of miR-488 in HCC cells and miR-488 inhibited the expression of HULC by sponging to HULC in HCC. Thus, our results suggest that miR-488 functions as a tumor suppressor in HCC and may be a potential target for HCC treatment.