bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α
Authors: Schönenberger Désirée , Harlander Sabine , Rajski Michal , Jacobs Robert A. , Lundby Anne-Kristine , Adlesic Mojca , Hejhal Tomas , Wild Peter J. , Lundby Carsten , Frew Ian J.
Published: March 2023

Abstract
The von Hippel–Lindau (VHL) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of Vhl alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1α has been implicated as a renal tumor suppressor, whereas HIF2α is considered an oncoprotein. In this study, we investigated the contributions of HIF1α and HIF2α to ccRCC initiation in the context of Vhl deficiency. We found that deleting Vhl plus Hif1a or Hif2a specifically in the renal epithelium did not induce tumor formation. However, HIF1α and HIF2α differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhl-deficient renal epithelial cells. HIF1α, but not HIF2α, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in Vhl mutant renal cells before ccRCC formation. Importantly, deletion of either Hif1a or Hif2a completely prevented the formation of renal cysts and tumors in Vhl/Trp53 mutant mice. These findings argue that both HIF1α and HIF2α exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney. Cancer Res; 76(7); 2025–36. ©2016 AACR.
Data from IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis
Authors: Brooks Gavin D. , McLeod Louise , Alhayyani Sultan , Miller Alistair , Russell Prudence A. , Ferlin Walter , Rose-John Stefan , Ruwanpura Saleela , Jenkins Brendan J.
Published: March 2023

Abstract
Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130F/F (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRAS-driven lung tumorigenesis. Malignant growths in the gp130F/F:KrasG12D model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental KrasG12D mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 trans-signaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma. Cancer Res; 76(4); 866–76. ©2016 AACR.
Data from Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgfβ/Smad Signaling
Authors: Yeo Syn Kok , Wen Jian , Chen Song , Guan Jun-Lin
Published: March 2023

Abstract
Cancer stem-like cells contribute to tumor heterogeneity and have been implicated in disease relapse and drug resistance. Here we show the coexistence of distinct breast cancer stem-like cells (BCSC) as identified by ALDH+ and CD29hiCD61+ markers, respectively, in murine models of breast cancer. While both BCSC exhibit enhanced tumor-initiating potential, CD29hiCD61+ BCSC displayed increased invasive abilities and higher expression of epithelial-to-mesenchymal transition and mammary stem cell–associated genes, whereas ALDH+ BCSC were more closely associated with luminal progenitors. Attenuating the autophagy regulator FIP200 diminished the tumor-initiating properties of both ALDH+ and CD29hiCD61+ BCSC, as achieved by impairing either the Stat3 or TGFβ/Smad pathways, respectively. Furthermore, combining the Stat3 inhibitor Stattic and the Tgfβ-R1 inhibitor LY-2157299 inhibited the formation of both epithelial and mesenchymal BCSC colonies. In vivo, this combination treatment was sufficient to limit tumor growth and reduce BCSC number. Overall, our findings reveal a differential dependence of heterogeneous BCSC populations on divergent signaling pathways, with implications on how to tailor drug combinations to improve therapeutic efficacy. Cancer Res; 76(11); 3397–410. ©2016 AACR.
Data from Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers
Authors: Morrison Joly Meghan , Hicks Donna J. , Jones Bayley , Sanchez Violeta , Estrada Monica Valeria , Young Christian , Williams Michelle , Rexer Brent N. , Sarbassov Dos D. , Muller William J. , Brantley-Sieders Dana , Cook Rebecca S.
Published: March 2023

Abstract
HER2 overexpression drives Akt signaling and cell survival and HER2-enriched breast tumors have a poor outcome when Akt is upregulated. Akt is activated by phosphorylation at T308 via PI3K and S473 via mTORC2. The importance of PI3K-activated Akt signaling is well documented in HER2-amplified breast cancer models, but the significance of mTORC2-activated Akt signaling in this setting remains uncertain. We report here that the mTORC2 obligate cofactor Rictor is enriched in HER2-amplified samples, correlating with increased phosphorylation at S473 on Akt. In invasive breast cancer specimens, Rictor expression was upregulated significantly compared with nonmalignant tissues. In a HER2/Neu mouse model of breast cancer, genetic ablation of Rictor decreased cell survival and phosphorylation at S473 on Akt, delaying tumor latency, penetrance, and burden. In HER2-amplified cells, exposure to an mTORC1/2 dual kinase inhibitor decreased Akt-dependent cell survival, including in cells resistant to lapatinib, where cytotoxicity could be restored. We replicated these findings by silencing Rictor in breast cancer cell lines, but not silencing the mTORC1 cofactor Raptor (RPTOR). Taken together, our findings establish that Rictor/mTORC2 signaling drives Akt-dependent tumor progression in HER2-amplified breast cancers, rationalizing clinical investigation of dual mTORC1/2 kinase inhibitors and developing mTORC2-specific inhibitors for use in this setting. Cancer Res; 76(16); 4752–64. ©2016 AACR.
Data from miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors
Authors: Bacci Marina , Giannoni Elisa , Fearns Antony , Ribas Ricardo , Gao Qiong , Taddei Maria Letizia , Pintus Gianfranco , Dowsett Mitch , Isacke Clare M. , Martin Lesley-Ann , Chiarugi Paola , Morandi Andrea
Published: March 2023

Abstract
Aromatase inhibitors (AI) have become the first-line endocrine treatment of choice for postmenopausal estrogen receptor–positive (ER+) breast cancer patients, but resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer and may contribute to drug resistance. Here, we investigated the link between altered breast cancer metabolism and AI resistance using AI-resistant and sensitive breast cancer cells, patient tumor samples, and AI-sensitive human xenografts. We found that long-term estrogen deprivation (LTED), a model of AI resistance, was associated with increased glycolysis dependency. Targeting the glycolysis-priming enzyme hexokinase-2 (HK2) in combination with the AI, letrozole, synergistically reduced cell viability in AI-sensitive models. Conversely, MCF7-LTED cells, which displayed a high degree of metabolic plasticity, switched to oxidative phosphorylation when glycolysis was impaired. This effect was ER dependent as breast cancer cells with undetectable levels of ER failed to exhibit metabolic plasticity. MCF7-LTED cells were also more motile than their parental counterparts and assumed amoeboid-like invasive abilities upon glycolysis inhibition with 2-deoxyglucose (2-DG). Mechanistic investigations further revealed an important role for miR-155 in metabolic reprogramming. Suppression of miR-155 resulted in sensitization of MCF7-LTED cells to metformin treatment and impairment of 2-DG–induced motility. Notably, high baseline miR-155 expression correlated with poor response to AI therapy in a cohort of ER+ breast cancers treated with neoadjuvant anastrozole. These findings suggest that miR-155 represents a biomarker potentially capable of identifying the subset of breast cancers most likely to adapt to and relapse on AI therapy. Cancer Res; 76(6); 1615–26. ©2016 AACR.
Data from ICOS Promotes the Function of CD4+ Effector T Cells during Anti-OX40–Mediated Tumor Rejection
Authors: Metzger Todd C. , Long Hua , Potluri Shobha , Pertel Thomas , Bailey-Bucktrout Samantha L. , Lin John C. , Fu Tihui , Sharma Padmanee , Allison James P. , Feldman Reid M.R.
Published: March 2023

Abstract
ICOS is a T-cell coregulatory receptor that provides a costimulatory signal to T cells during antigen-mediated activation. Antitumor immunity can be improved by ICOS-targeting therapies, but their mechanism of action remains unclear. Here, we define the role of ICOS signaling in antitumor immunity using a blocking, nondepleting antibody against ICOS ligand (ICOS-L). ICOS signaling provided critical support for the effector function of CD4+ Foxp3− T cells during anti-OX40–driven tumor immune responses. By itself, ICOS-L blockade reduced accumulation of intratumoral T regulatory cells (Treg), but it was insufficient to substantially inhibit tumor growth. Furthermore, it did not impede antitumor responses mediated by anti-4-1BB–driven CD8+ T cells. We found that anti-OX40 efficacy, which is based on Treg depletion and to a large degree on CD4+ effector T cell (Teff) responses, was impaired with ICOS-L blockade. In contrast, the provision of additional ICOS signaling through direct ICOS-L expression by tumor cells enhanced tumor rejection and survival when administered along with anti-OX40 therapy. Taken together, our results showed that ICOS signaling during antitumor responses acts on both Teff and Treg cells, which have opposing roles in promoting immune activation. Thus, effective therapies targeting the ICOS pathway should seek to promote ICOS signaling specifically in effector CD4+ T cells by combining ICOS agonism and Treg depletion. Cancer Res; 76(13); 3684–9. ©2016 AACR.
Data from Synergistic Activation of ERα by Estrogen and Prolactin in Breast Cancer Cells Requires Tyrosyl Phosphorylation of PAK1
Authors: Oladimeji Peter , Skerl Rebekah , Rusch Courtney , Diakonova Maria
Published: March 2023

Abstract
Serine/threonine kinase PAK1 is activated by estrogen and plays an important role in breast cancer. However, the integration of PAK1 into the estrogen response is not fully understood. In this study, we investigated the mechanisms underlying the hormone-induced activation of estrogen receptor (ERα, ESR1). We show that estrogen activated PAK1 through both the ERα and GPER1 membrane receptors. Estrogen-dependent activation of PAK1 required the phosphorylation of tyrosine residues by Etk/Bmx and protein kinase A (PKA) within an assembled signaling complex comprising pTyr-PAK1, Etk/Bmx, the heterotrimer G-protein subunits Gβ1, Gγ2, and/or Gγ5, PAK-associated guanine nucleotide exchange factor (βPIX, ARHGEF7), and PKA. Moreover, the PKA RIIβ subunit is a direct target of PAK1, and thus in response to estrogen, the activated pTyr-PAK1 complex reciprocally potentiated PKA activity, suggesting a positive feedback mechanism. We also demonstrate that PKA phosphorylated Ser305-ERα in response to estrogen, but pTyr-PAK1 phosphorylated Ser305-ERα in response to prolactin (PRL), implying that maximal ERα phosphorylation is achieved when cells are exposed to both PRL and estrogen. Furthermore, S305-ERα activation led to enhanced phosphorylation of Ser118-ERα and promoted cell proliferation and tumor growth. Together, these data strongly support a critical interplay between PRL and estrogen via PAK1 and suggest that ligand-independent activation of ERα through PRL/PAK1 may impart resistance to anti-estrogen therapies. Cancer Res; 76(9); 2600–11. ©2016 AACR.
Data from BPTF Depletion Enhances T-cell–Mediated Antitumor Immunity
Authors: Mayes Kimberly , Alkhatib Suehyb G. , Peterson Kristen , Alhazmi Aiman , Song Carolyn , Chan Vivian , Blevins Tana , Roberts Mark , Dumur Catherine I. , Wang Xiang-Yang , Landry Joseph W.
Published: March 2023

Abstract
Genetic studies in fruit flies have implicated the chromatin remodeling complex nucleosome remodeling factor (NURF) in immunity, but it has yet to be studied in mammals. Here we show that its targeting in mice enhances antitumor immunity in two syngeneic models of cancer. NURF was disabled by silencing of bromodomain PHD-finger containing transcription factor (BPTF), the largest and essential subunit of NURF. We found that both CD8+ and CD4+ T cells were necessary for enhanced antitumor activity, with elevated numbers of activated CD8+ T cells observed in BPTF-deficient tumors. Enhanced cytolytic activity was observed for CD8+ T cells cocultured with BPTF-silenced cells. Similar effects were not produced with T-cell receptor transgenic CD8+ T cells, implicating the involvement of novel antigens. Accordingly, enhanced activity was observed for individual CD8+ T-cell clones from mice bearing BPTF-silenced tumors. Mechanistic investigations revealed that NURF directly regulated the expression of genes encoding immunoproteasome subunits Psmb8 and Psmb9 and the antigen transporter genes Tap1 and Tap2. The PSMB8 inhibitor ONX-0914 reversed the effects of BPTF ablation, consistent with a critical role for the immunoproteasome in improving tumor immunogenicity. Thus, NURF normally suppresses tumor antigenicity and its depletion improves antigen processing, CD8 T-cell cytotoxicity, and antitumor immunity, identifying NURF as a candidate therapeutic target to enhance antitumor immunity. Cancer Res; 76(21); 6183–92. ©2016 AACR.
Data from TET1-Mediated Hypomethylation Activates Oncogenic Signaling in Triple-Negative Breast Cancer
Authors: Good Charly Ryan , Panjarian Shoghag , Kelly Andrew D. , Madzo Jozef , Patel Bela , Jelinek Jaroslav , Issa Jean-Pierre J.
Published: March 2023

Abstract
Both gains and losses of DNA methylation are common in cancer, but the factors controlling this balance of methylation remain unclear. Triple-negative breast cancer (TNBC), a subtype that does not overexpress hormone receptors or HER2/NEU, is one of the most hypomethylated cancers observed. Here, we discovered that the TET1 DNA demethylase is specifically overexpressed in about 40% of patients with TNBC, where it is associated with hypomethylation of up to 10% of queried CpG sites and a worse overall survival. Through bioinformatic analyses in both breast and ovarian cancer cell line panels, we uncovered an intricate network connecting TET1 to hypomethylation and activation of cancer-specific oncogenic pathways, including PI3K, EGFR, and PDGF. TET1 expression correlated with sensitivity to drugs targeting the PI3K–mTOR pathway, and CRISPR-mediated deletion of TET1 in two independent TNBC cell lines resulted in reduced expression of PI3K pathway genes, upregulation of immune response genes, and substantially reduced cellular proliferation, suggesting dependence of oncogenic pathways on TET1 overexpression. Our work establishes TET1 as a potential oncogene that contributes to aberrant hypomethylation in cancer and suggests that TET1 could serve as a druggable target for therapeutic intervention.

Significance: This study addresses a critical gap in knowledge of how and why methylation is prognostic in breast cancer and shows how this information can be used to stratify patients with TNBC for targeted therapy. Cancer Res; 78(15); 4126–37. ©2018 AACR.