Akt3 promotes cancer stemness in triple-negative breast cancer through YB1-Snail/Slug signaling axis.
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ABSTRACT:
SUBMITTER: Tian Y
PROVIDER: S-EPMC10201677 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
Publications
Akt3 promotes cancer stemness in triple-negative breast cancer through YB1-Snail/Slug signaling axis.
Tian Ye Y Li Jiang J Cheung Tsz Chung TC Tam Vincent V Lau C Geoffrey CG Wang Xin X Chin Y Rebecca YR
Genes & diseases 20220901 2
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Project description:Triple-negative breast cancer (TNBC) is currently the only major breast tumor subtype without effective targeted therapy and, as a consequence, in general has a poor outcome. To identify new therapeutic targets in TNBC, we performed a short hairpin RNA (shRNA) screen for protein kinases commonly amplified and overexpressed in breast cancer. Using this approach, we identified AKT3 as a gene preferentially required for the growth of TNBCs. Downregulation of Akt3 significantly inhibits the growth of TNBC lines in three-dimensional (3D) spheroid cultures and in mouse xenograft models, whereas loss of Akt1 or Akt2 have more modest effects. Akt3 silencing markedly upregulates the p27 cell-cycle inhibitor and this is critical for the ability of Akt3 to inhibit spheroid growth. In contrast with Akt1, Akt3 silencing results in only a minor enhancement of migration and does not promote invasion. Depletion of Akt3 in TNBC sensitizes cells to the pan-Akt inhibitor GSK690693. These results imply that Akt3 has a specific function in TNBCs; thus, its therapeutic targeting may provide a new treatment option for this tumor subtype.
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Project description:IMP3 (insulin-like growth factor-2 mRNA binding protein 3) is an oncofetal protein whose expression is prognostic for poor outcome in several cancers. Although IMP3 is expressed preferentially in triple-negative breast cancer (TNBC), its function is poorly understood. We observed that IMP3 expression is significantly higher in tumor initiating than in non-tumor initiating breast cancer cells and we demonstrate that IMP3 contributes to self-renewal and tumor initiation, properties associated with cancer stem cells (CSCs). The mechanism by which IMP3 contributes to this phenotype involves its ability to induce the stem cell factor SOX2. IMP3 does not interact with SOX2 mRNA significantly or regulate SOX2 expression directly. We discovered that IMP3 binds avidly to SNAI2 (SLUG) mRNA and regulates its expression by binding to the 5' UTR. This finding is significant because SLUG has been implicated in breast CSCs and TNBC. Moreover, we show that SOX2 is a transcriptional target of SLUG. These data establish a novel mechanism of breast tumor initiation involving IMP3 and they provide a rationale for its association with aggressive disease and poor outcome.
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Project description:Triple negative breast cancer (TNBC) is the most aggressive amongst all breast cancer (BC) subtypes. While TNBC tumors represent less than 20% of all BC subtypes, they are responsible for the most BC-related deaths. More significantly, when considering TNBC incidence across all racial/ethnic groups, TNBC accounts for less than 20% of all BCs. However, in non-Hispanic black women, the incidence rate of TNBC is more than 40%, which may be a contributing factor to the higher BC-related death rate in this population. These disparities remain strong even after accounting for differences in socioeconomic status, healthcare access, and lifestyle factors. Increased evidence now points to biological mechanisms that are intrinsic to the tumor that contribute to disparate TNBC disease burdens. Here, we show that YB1, a multifunction gene, plays a major role in the TNBC disparities between African American (AA) and Caucasian American (CA) women. We show in three independent TNBC tumors cohorts, that YB1 is significantly highly expressed in AA TNBC tumors when compared to CAs, and that increased levels of YB1 correlate with poor survival of AA patients with TNBC. We used a combination of genetic manipulation of YB1 and chemotherapy treatment, both in vitro and in animal models of TNBC to show that YB1 oncogenic activity is more enhanced in TNBC cell lines of AA origin, by increasing their tumorigenic and aggressive behaviors, trough the activation of cancer stem cell phenotype and resistance to chemotherapeutic treatments.
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Project description:BackgroundTreatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance.MethodsWe performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFβ2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models.ResultsIn vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFβ2-antisense 1 to promote TGFβ2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin.ConclusionTargeting the SRC-Slug-TGFβ2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs.
| S-EPMC11426005 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.
| S-EPMC11378519 | biostudies-literature
Project description:BACKGROUND:Triple-negative breast cancer (TNBC) is a poor prognostic breast cancer with the highest mutations and limited therapeutic choices. Cytokine networking between cancer cells and the tumor microenvironment (TME) maintains the self-renewing subpopulation of breast cancer stem cells (BCSCs) that mediate tumor heterogeneity, resistance and recurrence. Immunotherapy of those factors combined with targeted therapy or chemoagents may advantage TNBC treatment. RESULTS:We found that the oncogene Multiple Copies in T-cell Malignancy 1 (MCT-1/MCTS1) expression is a new poor-prognosis marker in patients with aggressive breast cancers. Overexpressing MCT-1 perturbed the oncogenic breast epithelial acini morphogenesis and stimulated epithelial-mesenchymal transition and matrix metalloproteinase activation in invasive TNBC cells, which were repressed after MCT-1 gene silencing. As mammary tumor progression was promoted by oncogenic MCT-1 activation, tumor-promoting M2 macrophages were enriched in TME, whereas M2 macrophages were decreased and tumor-suppressive M1 macrophages were increased as the tumor was repressed via MCT-1 knockdown. MCT-1 stimulated interleukin-6 (IL-6) secretion that promoted monocytic THP-1 polarization into M2-like macrophages to increase TNBC cell invasiveness. In addition, MCT-1 elevated the soluble IL-6 receptor levels, and thus, IL-6R antibodies antagonized the effect of MCT-1 on promoting M2-like polarization and cancer cell invasion. Notably, MCT-1 increased the features of BCSCs, which were further advanced by IL-6 but prevented by tocilizumab, a humanized IL-6R antibody, thus MCT-1 knockdown and tocilizumab synergistically inhibited TNBC stemness. Tumor suppressor miR-34a was induced upon MCT-1 knockdown that inhibited IL-6R expression and activated M1 polarization. CONCLUSIONS:The MCT-1 pathway is a novel and promising therapeutic target for TNBC.
| S-EPMC6421700 | biostudies-literature
Project description:The intricate relationship between tumor-associated macrophages (TAMs) and cancer cells is pivotal for carcinogenesis, with TAMs being integral to the tumor microenvironment (TME). This study explores the novel mechanisms by which TAMs regulate the progression of triple-negative breast cancer (TNBC) within the TME. Using a co-culture system and methodologies such as cytokine arrays, proteomics, and CRISPR-Cas9, we investigated the crosstalk between TAMs and TNBC cells. We found that high levels of CD163+ TAMs in TNBC tissues correlate with poor prognosis. TNBC cell-conditioned medium induces macrophage polarization towards the M2 phenotype, enhancing TNBC cell migration, invasion, and stemness through the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT). eNAMPT binding to CCR5 on TNBC cells activates STAT3, leading to the downregulation of the tumor suppressor DIRAS2 and an increase in CCL2, which promotes a macrophage recruitment loop. Intervention at the eNAMPT/CCR5 or CCL2 level disrupts this loop, mitigating TAM-induced effects. Our findings uncover a cytokine communication mechanism between immune and cancer cells, suggesting potential targets for TNBC detection and treatment.
| S-EPMC11900821 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B). PyVT-Ovol2 knockout mice develop a higher number of primary breast tumors with accelerated growth and increased lung-metastases. Furthermore, treatment with FAO inhibitors effectively reduces stemness characteristics of tumor cells, breast tumor initiation, and metastasis, especially in OVOL2-deficient breast tumors. The findings suggest that targeting JAK/STAT3 pathway and FAO is a promising therapeutic strategy for OVOL2-deficient TNBC.
| S-EPMC11199980 | biostudies-literature
Project description:BackgroundTriple-negative breast cancer (TNBC), as a subtype of breast cancer (BC), features an aggressive nature. Long noncoding RNAs (lncRNAs) are proved to get involved in the processes of cancers. lncRNA lung cancer associated transcript 1 (LUCAT1) has been reported in multiple cancers. The role of LUCAT1 in TNBC and its latent regulatory mechanism were investigated.MethodsRT-qPCR was performed to examine LUCAT1 expression. Functional experiments were implemented to disclose the role of LUCAT1 in TNBC. The underlying regulatory mechanism of LUCAT1 in TNBC was explored by chromatin immunoprecipitation (ChIP), RNA-binding protein immunoprecipitation (RIP), luciferase reporter, and RNA pull-down assays.ResultsLUCAT1 is significantly overexpressed in TNBC cells. LUCAT1 interference impedes cell stemness in TNBC cells. SRY-box transcription factor 2 (SOX2) is an active transcription factor of LUCAT1. LUCAT1 recruits ELAV-like RNA binding protein 1 (ELAVL1) protein to stabilize lin-28 homolog B (LIN28B) mRNA, thereby further modulating SOX2 expression, which forms a positive feedback loop.ConclusionThe lncRNA LUCAT1/ELAVL1/LIN28B/SOX2 positive feedback loop promotes cell stemness in TNBC. The exploration of the mechanisms underlying TNBC stemness might be beneficial to TNBC treatment.
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