bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Sustained Induction of c-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells
Authors: Parasido Erika , Avetian George S. , Naeem Aisha , Graham Garrett , Pishvaian Michael , Glasgow Eric , Mudambi Shaila , Lee Yichien , Ihemelandu Chukwuemeka , Choudhry Muhammad , Peran Ivana , Banerjee Partha P. , Avantaggiati Maria Laura , Bryant Kirsten , Baldelli Elisa , Pierobon Mariaelena , Liotta Lance , Petricoin Emanuel , Fricke Stanley T. , Sebastian Aimy , Cozzitorto Joseph , Loots Gabriela G. , Kumar Deepak , Byers Stephen , Londin Eric , DiFeo Analisa , Narla Goutham , Winter Jordan , Brody Jonathan R. , Rodriguez Olga , Albanese Chris
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel–resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the n-PTX-R cells. Depletion of c-MYC restored n-PTX sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small-molecule activator of protein phosphatase 2a.
Implications:
The strategies we have devised, including the patient-derived primary cells and the unique, drug-resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis.
Data from Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1
Authors: Indira Chandran Vineesh , Månsson Ann-Sofie , Barbachowska Magdalena , Cerezo-Magaña Myriam , Nodin Björn , Joshi Bharat , Koppada Neelima , Saad Ola M. , Gluz Oleg , Isaksson Karolin , Borgquist Signe , Jirström Karin , Nabi Ivan Robert , Jernström Helena , Belting Mattias
Published: March 2024

Abstract
The antibody–drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. We find that hypoxia fosters relative resistance to T-DM1 in HER2+ cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking.
Implications:
Together, our data for the first time identify hypoxic regulation of caveolin-1 as a resistance mechanism to T-DM1 with potential implications for individualized treatment of breast cancer.
Data from Targeting Opsin4/Melanopsin with a Novel Small Molecule Suppresses PKC/RAF/MEK/ERK Signaling and Inhibits Lung Adenocarcinoma Progression
Authors: Wang Qiushi , Zhang Tianshun , Chang Xiaoyu , Wang Keke , Lee Mee-Hyun , Ma Wei-Ya , Liu Kangdong , Dong Zigang
Published: March 2024

Abstract
The identification of oncogenic biomolecules as drug targets is an unmet need for the development of clinically effective novel anticancer therapies. In this study, we report for the first time that opsin 4/melanopsin (OPN4) plays a critical role in the pathogenesis of non–small cell lung cancer (NSCLC) and is a potential drug target. Our study has revealed that OPN4 is overexpressed in human lung cancer tissues and cells, and is inversely correlated with patient survival probability. Knocking down expression of OPN4 suppressed cells growth and induced apoptosis in lung cancer cells. We have also found that OPN4, a G protein-coupled receptor, interacted with Gα11 and triggered the PKC/BRAF/MEK/ERKs signaling pathway in lung adenocarcinoma cells. Genetic ablation of OPN4 attenuated the multiplicity and the volume of urethane-induced lung tumors in mice. Importantly, our study provides the first report of AE 51310 (1-[(2,5-dichloro-4-methoxyphenyl)sulfonyl]-3-methylpiperidine) as a small-molecule inhibitor of OPN4, suppressed the anchorage-independent growth of lung cancer cells and the growth of patient-derived xenograft tumors in mice.
Implications:
Overall, this study unveils the role of OPN4 in NSCLC and suggests that targeting OPN4 with small molecules, such as AE 51310 would be interesting to develop novel anticancer therapies for lung adenocarcinoma.
Data from Mapping of m6A and Its Regulatory Targets in Prostate Cancer Reveals a METTL3-Low Induction of Therapy Resistance
Authors: Cotter Kellie A. , Gallon John , Uebersax Nadine , Rubin Philip , Meyer Kate D. , Piscuoglio Salvatore , Jaffrey Samie R. , Rubin Mark A.
Published: March 2024

Abstract
Recent evidence has highlighted the role of N6-methyladenosine (m6A) in the regulation of mRNA expression, stability, and translation, supporting a potential role for posttranscriptional regulation mediated by m6A in cancer. Here, we explore prostate cancer as an exemplar and demonstrate that low levels of N6-adenosine-methyltransferase (METTL3) is associated with advanced metastatic disease. To investigate this relationship, we generated the first prostate m6A maps, and further examined how METTL3 regulates expression at the level of transcription, translation, and protein. Significantly, transcripts encoding extracellular matrix proteins are consistently upregulated with METTL3 knockdown. We also examined the relationship between METTL3 and androgen signaling and discovered the upregulation of a hepatocyte nuclear factor–driven gene signature that is associated with therapy resistance in prostate cancer. Significantly, METTL3 knockdown rendered the cells resistant to androgen receptor antagonists via an androgen receptor–independent mechanism driven by the upregulation of nuclear receptor NR5A2/LRH-1.
Implications:
These findings implicate changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer.
Data from TAGLN Is Downregulated by TRAF6-Mediated Proteasomal Degradation in Prostate Cancer Cells
Authors: Wen Fuping , Sun Xiaochen , Sun Chenxia , Dong Zhenyang , Jia Gaozhen , Bao Wei , Yu Haolan , Yang Chenghua
Published: March 2024

Abstract
Transgelin (TAGLN, also named SM22) is an actin-associated protein and affects dynamics of actin filaments. Deregulation of TAGLN contributes to the development of different cancers, and it is commonly considered to be a tumor suppressor. TAGLN is usually downregulated in prostate cancer; however, the detailed functions of TAGLN in prostate cancer and how TAGLN is regulated remains unclear. In this study, we confirmed that TAGLN is downregulated in prostate cancer tissues and demonstrated that the downregulation of TAGLN occurs through proteasomal degradation. Next, we found that the expression level of TAGLN is inversely correlated with TRAF6. We screened more than 20 E2–E3 pairs by in vitro ubiquitination assay and found that the E2A–TRAF6 pair catalyzed mono ubiquitination of TAGLN. We then identified the ubiquitination sites of TAGLN to be on K89 or K108 residues and demonstrated that ubiquitination of TAGLN on K89/K108 are important for TRAF6-mediated proteasomal degradation. Furthermore, we investigated the function of TAGLN in prostate cancer cells. We found that ablation of TAGLN promoted prostate cancer cell proliferation and suppressed their migration via activation of NF-κB and Myc signaling pathways. Overall, our study provided new insights into the mechanisms underlying TAGLN expression and activity in prostate cancer.
Implications:
E3 ligase TRAF6 mediate mono-ubiquitination and degradation of TAGLN, which leads to activation of NF-κB and Myc signaling pathways in prostate cancer cells.
Data from Paracrine Placental Growth Factor Signaling in Response to Ionizing Radiation Is p53-Dependent and Contributes to Radioresistance
Authors: Kazimova Tamara , Tschanz Fabienne , Sharma Ashish , Telarovic Irma , Wachtel Marco , Pedot Gloria , Schäfer Beat , Pruschy Martin
Published: March 2024

Abstract
Placental growth factor (PlGF) is a pro-angiogenic, N-glycosylated growth factor, which is secreted under pathologic situations. Here, we investigated the regulation of PlGF in response to ionizing radiation (IR) and its role for tumor angiogenesis and radiosensitivity. Secretion and expression of PlGF was induced in multiple tumor cell lines (medulloblastoma, colon and lung adenocarcinoma) in response to irradiation in a dose- and time-dependent manner. Early upregulation of PlGF expression and secretion in response to irradiation was primarily observed in p53 wild-type tumor cells, whereas tumor cells with mutated p53 only showed a minimal or delayed response. Mechanistic investigations with genetic and pharmacologic targeting of p53 corroborated regulation of PlGF by the tumor suppressor p53 in response to irradiation under normoxic and hypoxic conditions, but with so far unresolved mechanisms relevant for its minimal and delayed expression in tumor cells with a p53-mutated genetic background. Probing a paracrine role of IR-induced PlGF secretion in vitro, migration of endothelial cells was specifically increased towards irradiated PlGF wild type but not towards irradiated PlGF-knockout (PIGF-ko) medulloblastoma cells. Tumors derived from these PlGF-ko cells displayed a reduced growth rate, but similar tumor vasculature formation as in their wild-type counterparts. Interestingly though, high-dose irradiation strongly reduced microvessel density with a concomitant high rate of complete tumor regression only in the PlGF-ko tumors.
Implications:
Our study shows a strong paracrine vasculature-protective role of PlGF as part of a p53-regulated IR-induced resistance mechanism and suggest PlGF as a promising target for a combined treatment modality with RT.
Data from Platinum-Induced Ubiquitination of Phosphorylated H2AX by RING1A Is Mediated by Replication Protein A in Ovarian Cancer
Authors: Sriramkumar Shruthi , Matthews Timothy D. , Ghobashi Ahmed H. , Miller Samuel A. , VanderVere-Carozza Pamela S. , Pawelczak Katherine S. , Nephew Kenneth P. , Turchi John J. , O'Hagan Heather M.
Published: March 2024

Abstract
Platinum resistance is a common occurrence in high-grade serous ovarian cancer and a major cause of ovarian cancer deaths. Platinum agents form DNA cross-links, which activate nucleotide excision repair (NER), Fanconi anemia, and homologous recombination repair (HRR) pathways. Chromatin modifications occur in the vicinity of DNA damage and play an integral role in the DNA damage response (DDR). Chromatin modifiers, including polycomb repressive complex 1 (PRC1) members, and chromatin structure are frequently dysregulated in ovarian cancer and can potentially contribute to platinum resistance. However, the role of chromatin modifiers in the repair of platinum DNA damage in ovarian cancer is not well understood. We demonstrate that the PRC1 complex member RING1A mediates monoubiquitination of lysine 119 of phosphorylated H2AX (γH2AXub1) at sites of platinum DNA damage in ovarian cancer cells. After platinum treatment, our results reveal that NER and HRR both contribute to RING1A localization and γH2AX monoubiquitination. Importantly, replication protein A, involved in both NER and HRR, mediates RING1A localization to sites of damage. Furthermore, RING1A deficiency impairs the activation of the G2–M DNA damage checkpoint, reduces the ability of ovarian cancer cells to repair platinum DNA damage, and increases sensitivity to platinum.
Implications:
Elucidating the role of RING1A in the DDR to platinum agents will allow for the identification of therapeutic targets to improve the response of ovarian cancer to standard chemotherapy regimens.
Data from Aberrant Claudin-6–Adhesion Signaling Promotes Endometrial Cancer Progression via Estrogen Receptor α
Authors: Kojima Manabu , Sugimoto Kotaro , Kobayashi Makoto , Ichikawa-Tomikawa Naoki , Kashiwagi Korehito , Watanabe Takafumi , Soeda Shu , Fujimori Keiya , Chiba Hideki
Published: March 2024

Abstract
Cell adhesion proteins not only maintain tissue integrity, but also possess signaling abilities to organize diverse cellular events in a variety of physiologic and pathologic processes; however, the underlying mechanism remains obscure. Among cell adhesion molecules, the claudin (CLDN) family is often aberrantly expressed in various cancers, but the biological relevance and molecular basis for this observation have not yet been established. Here, we show that high CLDN6 expression accelerates cellular proliferation and migration in two distinct human endometrial cancer cell lines in vitro. Using a xenograft model, we also revealed that aberrant CLDN6 expression promotes tumor growth and invasion in endometrial cancer tissues. The second extracellular domain and Y196/200 of CLDN6 were required to recruit and activate Src-family kinases (SFK) and to stimulate malignant phenotypes. Knockout and overexpression of ESR1 in endometrial carcinoma cells showed that the CLDN6-adhesion signal links to estrogen receptor α (ERα) to advance tumor progression. In particular, aberrant CLDN6–ERα signaling contributed to collective cell behaviors in the leading front of endometrial cancer cells. Importantly, we demonstrate that CLDN6/SFK/PI3K-dependent AKT and SGK (serum- and glucocorticoid-regulated kinase) signaling in endometrial cancer cells targets Ser518 in the human ERα to activate ERα transcriptional activity in a ligand-independent manner, thereby promoting tumor progression. Furthermore, CLDN6, at least in part, also regulated gene expression in an ERα-independent manner.
Implications:
The identification of this machinery highlights regulation of the transcription factors by cell adhesion to advance tumor progression.
Data from Colorectal Cancer-Associated Smad4 R361 Hotspot Mutations Boost Wnt/β-Catenin Signaling through Enhanced Smad4–LEF1 Binding
Authors: Lanauze Claudia B. , Sehgal Priyanka , Hayer Katharina , Torres-Diz Manuel , Pippin James A. , Grant Struan F.A. , Thomas-Tikhonenko Andrei
Published: March 2024

Abstract
About 10% to 30% of patients with colorectal cancer harbor either loss of or missense mutations in SMAD4, a critical component of the TGFβ signaling pathway. The pathophysiologic function of missense mutations in Smad4 is not fully understood. They usually map to the MH2 domain, specifically to residues that are involved in heterodimeric complex formation with regulatory Smads (such as Smad2/3) and ensuing transcriptional activation. These detrimental effects suggest that SMAD4 missense mutations can be categorized as loss-of-function. However, they tend to cluster in a few hotspots, which is more consistent with them acting by a gain-of-function mechanism. In this study, we investigated the functional role of Smad4 R361 mutants by re-expressing two R361 Smad4 variants in several Smad4-null colorectal cancer cell lines. As predicted, R361 mutations disrupted Smad2/3-Smad4 heteromeric complex formation and abolished canonical TGFβ signaling. In that, they were similar to SMAD4 loss. However, RNA sequencing and subsequent RT-PCR assays revealed that Smad4mut cells acquired a gene signature associated with enhanced Lef1 protein function and increased Wnt signaling. Mechanistically, Smad4 mutant proteins retained binding to Lef1 protein and drove a commensurate increase in downstream Wnt signaling as measured by TOP/FOP luciferase assay and Wnt-dependent cell motility. Consistent with these findings, human colorectal cancers with SMAD4 missense mutations were less likely to acquire activating mutations in the key Wnt pathway gene CTNNB1 (encoding β-catenin) than colorectal cancers with truncating SMAD4 nonsense mutations.
Implications:
Our studies suggest that in colorectal cancer hotspot mutations in Smad4 confer enhanced Wnt signaling and possibly heightened sensitivity to Wnt pathway inhibitors.
Data from MicroRNA-324-5p–CUEDC2 Axis Mediates Gain-of-Function Mutant p53-Driven Cancer Stemness
Authors: Ghatak Dishari , Datta Arindam , Roychowdhury Tanaya , Chattopadhyay Samit , Roychoudhury Susanta
Published: March 2024

Abstract
Regulation of cancer stemness has recently emerged as a new gain-of-function (GOF) property of mutant p53. In this study, we identify miR-324-5p as a critical epigenetic regulator of cancer stemness and demonstrate its role in mediating GOF-mutant p53-driven stemness phenotypes. We report that miR-324–5p is upregulated in human cancer cell lines and non–small cell lung carcinoma (NSCLC) tumors carrying TP53 GOF mutations. Mechanistically, we show that GOF mutant p53 upregulates miR-324–5p expression via c-Myc, an oncogenic transcription factor in cancer cells. Our experimental results suggest that miR-324–5p–induced CSC phenotypes stem from the downregulation of CUEDC2, a downstream target gene of miR-324–5p. Accordingly, CUEDC2 complementation diminishes elevated CSC marker expression in miR-324–5p–overexpressing cancer cells. We further demonstrate that mutant p53 cancer cells maintain a low level of CUEDC2 that is rescued upon miR-324–5p inhibition. Importantly, we identify CUEDC2 downregulation as a novel characteristic feature of TP53-mutated human cancers. We show that activation of NF-κB due to downregulation of CUEDC2 by miR-324–5p imparts stemness in GOF mutant p53 cancer cells. Finally, we provide evidence that TP53 mutations coupled with high miR-324–5p expression predict poor prognosis in patients with lung adenocarcinoma. Thus, our study delineates an altered miR-324–5p-CUEDC2-NF-κB pathway as a novel regulator of GOF mutant p53-driven cancer stemness.
Implications:
Our findings implicate miRNA-324–5p as a novel epigenetic modifier of human cancer stemness.
Data from HDAC3 Is Required for XPC Recruitment and Nucleotide Excision Repair of DNA Damage Induced by UV Irradiation
Authors: Nishimoto Koji , Niida Hiroyuki , Uchida Chiharu , Ohhata Tatsuya , Kitagawa Kyoko , Motegi Akira , Suda Takafumi , Kitagawa Masatoshi
Published: March 2024

Abstract
Recent studies have demonstrated that lysine acetylation of histones is crucial for nucleotide excision repair (NER) by relaxing the chromatin structure, which facilitates the recruitment of repair factors. However, few studies have focused on the contribution of histone deacetylases (HDAC) to NER. Here, we found that histone H3 Lys14 (H3K14) was deacetylated by HDAC3 after UV irradiation. Depletion of HDAC3 caused defects in cyclobutene pyrimidine dimer excision and sensitized cells to UV irradiation. HDAC3-depleted cells had impaired unscheduled DNA synthesis, but not recovery of RNA synthesis, which indicates that HDAC3 was required for global genome NER. Moreover, xeroderma pigmentosum, complementation group C (XPC) accumulation at the local UV-irradiated area was attenuated in HDAC3-depleted cells. In addition to the delay of XPC accumulation at DNA damage sites, XPC ubiquitylation was inhibited in HDAC3-depleted cells. These results suggest that the deacetylation of histone H3K14 by HDAC3 after UV irradiation contributes to XPC recruitment to DNA lesions to promote global genome NER.
Implications:
Involvement of histone deacetylation for XPC accumulation after UV irradiation indicates conversion of chromatin structure is essential for nucleotide excision repair in human cancer cells.
Data from SGK2, 14-3-3, and HUWE1 Cooperate to Control the Localization, Stability, and Function of the Oncoprotein PTOV1
Authors: Pennington Katie L. , McEwan Colten M. , Woods James , Muir Colin M. , Pramoda Sahankumari A.G. , Eastmond Riley , Balasooriya Eranga R. , Egbert Christina M. , Kaur Sandeep , Heaton Tyler , McCormack Katherine K. , Piccolo Stephen R. , Kurokawa Manabu , Andersen Joshua L.
Published: March 2024

Abstract
PTOV1 is an oncogenic protein, initially identified in prostate cancer, that promotes proliferation, cell motility, and invasiveness. However, the mechanisms that regulate PTOV1 remain unclear. Here, we identify 14-3-3 as a PTOV1 interactor and show that high levels of 14-3-3 expression, like PTOV1, correlate with prostate cancer progression. We discover an SGK2-mediated phosphorylation of PTOV1 at S36, which is required for 14-3-3 binding. Disruption of the PTOV1–14–3-3 interaction results in an accumulation of PTOV1 in the nucleus and a proteasome-dependent reduction in PTOV1 protein levels. We find that loss of 14-3-3 binding leads to an increase in PTOV1 binding to the E3 ubiquitin ligase HUWE1, which promotes proteasomal degradation of PTOV1. Conversely, our data suggest that 14-3-3 stabilizes PTOV1 protein by sequestering PTOV1 in the cytosol and inhibiting its interaction with HUWE1. Finally, our data suggest that stabilization of the 14-3-3–bound form of PTOV1 promotes PTOV1-mediated expression of cJun, which drives cell-cycle progression in cancer. Together, these data provide a mechanism to understand the regulation of the oncoprotein PTOV1.
Implications:
These findings identify a potentially targetable mechanism that regulates the oncoprotein PTOV1.
Data from Loss of E-cadherin Induces IGF1R Activation and Reveals a Targetable Pathway in Invasive Lobular Breast Carcinoma
Authors: Elangovan Ashuvinee , Hooda Jagmohan , Savariau Laura , Puthanmadhomnarayanan Susrutha , Yates Megan E. , Chen Jian , Brown Daniel D. , McAuliffe Priscilla F. , Oesterreich Steffi , Atkinson Jennifer M. , Lee Adrian V.
Published: March 2024

Abstract
No special-type breast cancer [NST; commonly known as invasive ductal carcinoma (IDC)] and invasive lobular carcinoma (ILC) are the two major histological subtypes of breast cancer with significant differences in clinicopathological and molecular characteristics. The defining pathognomonic feature of ILC is loss of cellular adhesion protein, E-cadherin (CDH1). We have previously shown that E-cadherin functions as a negative regulator of the IGF1R and propose that E-cadherin loss in ILC sensitizes cells to growth factor signaling that thus alters their sensitivity to growth factor–signaling inhibitors and their downstream activators. To investigate this potential therapeutic vulnerability, we generated CRISPR-mediated CDH1 knockout (CDH1 KO) IDC cell lines (MCF7, T47D, and ZR75.1) to uncover the mechanism by which loss of E-cadherin results in IGF pathway activation. CDH1 KO cells demonstrated enhanced invasion and migration that was further elevated in response to IGF1, serum and collagen I. CDH1 KO cells exhibited increased sensitivity to IGF resulting in elevated downstream signaling. Despite minimal differences in membranous IGF1R levels between wild-type (WT) and CDH1 KO cells, significantly higher ligand–receptor interaction was observed in the CDH1 KO cells, potentially conferring enhanced downstream signaling activation. Critically, increased sensitivity to IGF1R, PI3K, Akt, and MEK inhibitors was observed in CDH1 KO cells and ILC patient-derived organoids.
Implications:
Overall, this suggests that these targets require further exploration in ILC treatment and that CDH1 loss may be exploited as a biomarker of response for patient stratification.
Data from VPRBP Functions Downstream of the Androgen Receptor and OGT to Restrict p53 Activation in Prostate Cancer
Authors: Poulose Ninu , Forsythe Nicholas , Polonski Adam , Gregg Gemma , Maguire Sarah , Fuchs Marc , Minner Sarah , Sauter Guido , McDade Simon S. , Mills Ian G.
Published: March 2024

Abstract
Androgen receptor (AR) is a major driver of prostate cancer initiation and progression. O-GlcNAc transferase (OGT), the enzyme that catalyzes the covalent addition of UDP-N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of proteins, is often highly expressed in prostate cancer with its expression correlated with high Gleason score. In this study, we have identified an AR and OGT coregulated factor, Vpr (HIV-1) binding protein (VPRBP) also known as DDB1 and CUL4 Associated Factor 1 (DCAF1). We show that VPRBP is regulated by the AR at the transcript level, and stabilized by OGT at the protein level. VPRBP knockdown in prostate cancer cells led to a significant decrease in cell proliferation, p53 stabilization, nucleolar fragmentation, and increased p53 recruitment to the chromatin. In human prostate tumor samples, VPRBP protein overexpression correlated with AR amplification, OGT overexpression, a shorter time to postoperative biochemical progression and poor clinical outcome. In clinical transcriptomic data, VPRBP expression was positively correlated with the AR and also with AR activity gene signatures.
Implications:
In conclusion, we have shown that VPRBP/DCAF1 promotes prostate cancer cell proliferation by restraining p53 activation under the influence of the AR and OGT.
Data from Phosphoproteomics Reveals the Role of Constitutive KAP1 Phosphorylation by B-cell Receptor Signaling in Chronic Lymphocytic Leukemia
Authors: Wu Jung-Lin , Wu Hsin-Yi , Wu Shang-Ju , Tsai Ho-Yang , Weng Shao-Hsing , Lin Kuen-Tyng , Lin Liang-In , Yao Chi-Yuan , Zamanova Margarita , Lee Yi-Yuan , Angata Takashi , Tien Hwei-Fang , Chen Yu-Ju , Lin Kuo-I
Published: March 2024

Abstract
Application of B-cell receptor (BCR) pathway inhibitor ibrutinib for chronic lymphocytic leukemia (CLL) is a major breakthrough, yet the downstream effects following inhibition of BCR signaling and during relapse await further clarification. By comparative phosphoproteomic profiling of B cells from patients with CLL and healthy donors, as well as CLL B cells collected at multiple time points during the course of ibrutinib treatment, we provided the landscape of dysregulated phosphoproteome in CLL and its dynamic alterations associated with ibrutinib treatment. Particularly, differential phosphorylation events associated with several signaling pathways, including BCR pathway, were enriched in patient CLL cells. A constitutively elevated phosphorylation level of KAP1 at serine 473 (S473) was found in the majority of CLL samples prior to treatment. Further verification showed that BCR activation promoted KAP1 S473 phosphorylation, whereas ibrutinib treatment abolished it. Depletion of KAP1 in primary CLL cells decelerated cell-cycle progression and ectopic expression of a KAP1 S473 phospho-mimicking mutant accelerated G2–M cell-cycle transition of CLL cells. Moreover, temporal phosphoproteomic profiles using a series of CLL cells isolated from one patient during the ibrutinib treatment revealed the dynamic changes of several molecules associated with BCR signaling in the ibrutinib responsive and recurrent stages.
Implications:
This phosphoproteomic analysis and functional validation illuminated the phosphorylation of KAP1 at S473 as an important downstream BCR signaling event and a potential indicator for the success of ibrutinib treatment in CLL.
Data from A Druggable UHRF1/DNMT1/GLI Complex Regulates Sonic Hedgehog–Dependent Tumor Growth
Authors: Yang Fan , Rodriguez-Blanco Jezabel , Long Jun , Swiderska-Syn Marzena , Wynn Daniel T. , Li Bin , Shen Chen , Nayak Anmada , Ban Yuguang , Sun Xiaodian , Suter Robert K. , McCrea Heather J. , Capobianco Anthony J. , Ayad Nagi G. , Robbins David J.
Published: March 2024

Abstract
Dysregulation of Sonic hedgehog (SHH) signaling drives the growth of distinct cancer subtypes, including medulloblastoma (MB). Such cancers have been treated in the clinic with a number of clinically relevant SHH inhibitors, the majority of which target the upstream SHH regulator, Smoothened (SMO). Despite considerable efficacy, many of these patients develop resistance to these drugs, primarily due to mutations in SMO. Therefore, it is essential to identify druggable, signaling components downstream of SMO to target in SMO inhibitor resistant cancers. We utilized an integrated functional genomics approach to identify epigenetic regulators of SHH signaling and identified a novel complex of Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), DNA methyltransferase 1 (DNMT1), and GLI proteins. We show that this complex is distinct from previously described UHRF1/DNMT1 complexes, suggesting that it works in concert to regulate GLI activity in SHH driven tumors. Importantly, we show that UHRF1/DNMT1/GLI complex stability is targeted by a repurposed FDA-approved therapy, with a subsequent reduction in the growth of SHH-dependent MB ex vivo and in vivo.
Implications:
This work describes a novel, druggable UHRF1/DNMT1/GLI complex that regulates SHH-dependent tumor growth, and highlights an FDA-approved drug capable of disrupting this complex to attenuate tumor growth.
Data from Single Nucleotide Polymorphism–Based Genome-Wide Chromosome Copy Change, Loss of Heterozygosity, and Aneuploidy in Barrett's Esophagus Neoplastic Progression
Authors: Li Xiaohong , Galipeau Patricia C. , Sanchez Carissa A. , Blount Patricia L. , Maley Carlo C. , Arnaudo Jessica , Peiffer Daniel A. , Pokholok Dmitry , Gunderson Kevin L. , Reid Brian J.
Published: March 2024

Abstract
Chromosome copy gain, loss, and loss of heterozygosity (LOH) involving most chromosomes have been reported in many cancers; however, less is known about chromosome instability in premalignant conditions. 17p LOH and DNA content abnormalities have been previously reported to predict progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA). Here, we evaluated genome-wide chromosomal instability in multiple stages of BE and EA in whole biopsies. Forty-two patients were selected to represent different stages of progression from BE to EA. Whole BE or EA biopsies were minced, and aliquots were processed for flow cytometry and genotyped with a paired constitutive control for each patient using 33,423 single nucleotide polymorphisms (SNP). Copy gains, losses, and LOH increased in frequency and size between early- and late-stage BE (P < 0.001), with SNP abnormalities increasing from <2% to >30% in early and late stages, respectively. A set of statistically significant events was unique to either early or late, or both, stages, including previously reported and novel abnormalities. The total number of SNP alterations was highly correlated with DNA content aneuploidy and was sensitive and specific to identify patients with concurrent EA (empirical receiver operating characteristic area under the curve = 0.91). With the exception of 9p LOH, most copy gains, losses, and LOH detected in early stages of BE were smaller than those detected in later stages, and few chromosomal events were common in all stages of progression. Measures of chromosomal instability can be quantified in whole biopsies using SNP-based genotyping and have potential to be an integrated platform for cancer risk stratification in BE.
Data from A Strong Case for Personalized, Targeted Cancer Prevention
Authors: Dawson Marcia I.
Published: March 2024

Abstract
The study reported by Lee and colleagues in this issue of the journal (beginning on page 185) incorporated global genetic variation within a new assessment of the outcome of a previously reported phase-III trial of low-dose 13-cis-retinoic acid (13-cRA) for preventing second primary tumors (SPT) or the recurrence of head-and-neck cancer. This analysis identified genotypes of common single-nucleotide polymorphisms (SNP) and cumulative effect and potential gene–gene interactions that were highly associated with increased placebo-arm risk (prognostic) and/or with reduced treatment-arm risk and longer event-free survival (predictive). For example, the wild-type rs3118570 SNP of the retinoid X receptor alpha gene (carried by 71% of the 13-cRA trial population) marked a 3.33-fold increased SPT/recurrence risk in the placebo arm and a 38% reduced risk in the treatment arm. Adding two other informative genotypes strengthened the treatment-arm risk reduction to 76%, although the genotype trio reflected only 13% of the trial population. This report extends the concept of personalized therapy to cancer prevention. Cancer Prev Res; 4(2); 173–6. ©2011 AACR.
Data from Association between Urinary Prostaglandin E2 Metabolite and Breast Cancer Risk: A Prospective, Case–Cohort Study of Postmenopausal Women
Authors: Kim Sangmi , Taylor Jack A. , Milne Ginger L. , Sandler Dale P.
Published: March 2024

Abstract
Overweight or obese women are at increased risk of developing and dying from breast cancer. Obesity-driven inflammation may stimulate prostaglandin E2 (PGE2)-mediated aromatase activation and estrogen biosynthesis in breast tissues. We hypothesized that increased production of PGE2 would contribute to elevated breast cancer risk in postmenopausal women. We carried out a case–cohort study with 307 incident breast cancer cases and 300 subcohort members from the Sister Study cohort. HRs and 95% confidence intervals (CI) were estimated for the association between urinary levels of a major PGE2 metabolite (PGE-M) and breast cancer risk using Prentice's pseudo-likelihood approach. Several lifestyle factors were associated with urinary levels of PGE-M: smoking, high-saturated fat diet, and obesity increased urinary PGE-M, and use of nonsteroidal antiinflammatory drugs (NSAID) decreased urinary PGE-M. Although there was no association between urinary PGE-M and postmenopausal breast cancer risk in the overall analysis or among regular users of NSAIDs, there was a positive association among postmenopausal women who did not regularly use NSAIDs with HRs of 2.1 [95% confidence interval (CI): 1.0–4.3]; 2.0 (95% CI: 1.0–3.9); and 2.2 (95% CI: 1.1–4.3) for the second, third, and highest quartiles of PGE-M. Our findings suggest a link between systemic PGE2 formation and postmenopausal breast cancer, and a possible modification of the association by lifestyle and pharmacologic interventions. If confirmed in larger studies, these results may have useful implications for the development of preventive strategies. Cancer Prev Res; 6(6); 511–8. ©2013 AACR.
Data from Neonatal Experiences Differentially Influence Mammary Gland Morphology, Estrogen Receptor α Protein Levels, and Carcinogenesis in BALB/c Mice
Authors: Boyd Allison L. , Salleh Ayesha , Humber Brent , Yee Janet , Tomes Ladislav , Kerr Leslie R.
Published: March 2024

Abstract
Prevention of breast cancer can be achieved with a better understanding of the factors contributing to normal breast development. Because the breast develops postnatally, alterations in the development and lifetime activity of the neuroendocrine system may set up an environment that increases cancer risk. The present study examined how two neonatal experiences over the first 3 weeks of life influence normal and malignant mammary gland development in female BALB/c mice. Following puberty, both brief (15 minutes) and prolonged (4 hours) daily maternal separations of newborn mice accelerated mammary gland development relative to nonseparated mice. Despite similar mammary gland morphologies between mice exposed to these two neonatal separation experiences, only mice exposed to prolonged maternal separation bouts showed a higher incidence and faster onset of mammary tumorigenesis following adulthood carcinogen [7,12-dimethylbenz(a)anthracene] administration. Molecular analysis of estrogen receptor α (ERα) and p53, two proteins that have been implicated in breast cancer, revealed that for mice exposed to prolonged neonatal maternal separation bouts, mammary gland ERα protein levels were upregulated in a transcription-independent manner. On the other hand, p53 expression in mammary glands of adult mice was not differentially influenced by neonatal experiences. Our findings show that chronic, moderate psychosocial stress during the neonatal period increases the expression of ERα protein and promotes mammary tumorigenesis in adulthood. Cancer Prev Res; 3(11); 1398–408. ©2010 AACR.
Data from Dietary Energy Balance Modulates Epithelial-to-Mesenchymal Transition and Tumor Progression in Murine Claudin-Low and Basal-like Mammary Tumor Models
Authors: Dunlap Sarah M. , Chiao Lucia J. , Nogueira Leticia , Usary Jerry , Perou Charles M. , Varticovski Lyuba , Hursting Stephen D.
Published: March 2024

Abstract
Using novel murine models of claudin-low and basal-like breast cancer, we tested the hypothesis that diet-induced obesity (DIO) and calorie restriction (CR) differentially modulate progression of these aggressive breast cancer subtypes. For model development, we characterized two cell lines, “mesenchymal (M)-Wnt” and “epithelial (E)-Wnt,” derived from MMTV-Wnt-1 transgenic mouse mammary tumors. M-Wnt, relative to E-Wnt, cells were tumor-initiating cell (TIC)-enriched (62% vs. 2.4% CD44high/CD24low) and displayed enhanced ALDEFLUOR positivity, epithelial-to-mesenchymal transition (EMT) marker expression, mammosphere-forming ability, migration, invasion, and tumorigenicity (P < 0.001; each parameter). M-Wnt and E-Wnt cells clustered with claudin-low and basal-like breast tumors, respectively, in gene expression profiles and recapitulated these tumors when orthotopically transplanted into ovariectomized C57BL/6 mice. To assess the effects of energy balance interventions on tumor progression and EMT, mice were administered DIO, control, or CR diets for 8 weeks before orthotopic transplantation of M-Wnt or E-Wnt cells (for each cell line, n = 20 mice per diet) and continued on their diets for 6 weeks while tumor growth was monitored. Relative to control, DIO enhanced M-Wnt (P = 0.01), but not E-Wnt, tumor progression; upregulated EMT- and TIC-associated markers including N-cadherin,fibronectin, TGFβ, Snail, FOXC2, and Oct4 (P < 0.05, each); and increased intratumoral adipocytes. Conversely, CR suppressed M-Wnt and E-Wnt tumor progression (P < 0.02, each) and inhibited EMT and intratumoral adipocyte accumulation. Thus, dietary energy balance interventions differentially modulate EMT and progression of claudin-low and basal-like tumors. EMT pathway components may represent targets for breaking the obesity–breast cancer link, particularly for preventing and/or controlling TIC-enriched subtypes such as claudin-low breast cancer. Cancer Prev Res; 5(7); 930–42. ©2012 AACR.
Data from Molecular Biomarkers of Risk in Premalignancy and Breast Cancer Prevention
Authors: Allred D. Craig
Published: March 2024

Abstract
About 50,000 U.S. women are diagnosed with breast atypical hyperplasia each year, giving them about a six-fold increased relative risk of developing invasive breast cancer (IBC) compared with age-matched controls. Still, only a small fraction of patients with atypical hyperplasia ever progress to IBC, which is a major reason why a large majority do not participate in breast cancer prevention, despite the remarkable effectiveness of currently available risk-reducing therapies. An interesting study reported by Radisky and colleagues in this issue of the journal (beginning on page 1953) evaluated expression levels of p16ink4a in atypical hyperplasia for more accurately predicting risk—hoping to identify high-risk patients who will benefit most from therapy while sparing those with lower risk from unnecessary therapy. Unfortunately, p16ink4a expression was not prognostic in this particular study, although research to identify powerful biomarkers of risk remains a high priority. Fortunately, there are many other promising biomarkers under investigation, as well as several underutilized experimental strategies which could help promote successful breast cancer prevention. Cancer Prev Res; 4(12); 1947–52. ©2011 AACR.
Data from Opportunities for the Primary Prevention of Colorectal Cancer in the United States
Authors: Joshu Corinne E. , Parmigiani Giovanni , Colditz Graham A. , Platz Elizabeth A.
Published: March 2024

Abstract
Several studies indicate that screening in combination with lifestyle modification may produce a greater reduction in colorectal cancer rates than screening alone. To identify national opportunities for the primary prevention of colorectal cancer, we assessed the prevalence of modifiable lifestyle risk factors in the United States. We used nationally representative, cross-sectional data from 5 NHANES cycles (1999–2000, n = 2,753; 2001–2002, n = 3,169; 2003–2004, n = 2,872; 2005–2006, n = 2,993; 2007–2008, n = 3,438). We evaluated the 5 colorectal cancer risk factors deemed “convincing” by the World Cancer Research Fund (obesity, physical inactivity, intake of red meat, processed meat, alcohol), and cigarette smoking, a “suggestive” risk factor in the Surgeon General's report. We estimated the prevalence of each risk factor separately and jointly, and report it overall, and by sex, race/ethnicity, age, and year. In 2007 to 2008, 81% percent of U.S. adults, aged 20 to 69 years, had at least one modifiable risk factor for colorectal cancer. More than 15% of those younger than 50 years had 3 or more risk factors. There was no change in the prevalence of risk factors between 1999 and 2008. The most common risk factors were risk factors for other chronic diseases. Our findings provide additional support for the prioritization of preventive services in health care reform. Increasing awareness, especially among young adults, that lifestyle factors influence colorectal cancer risk, and other chronic diseases, may encourage lifestyle changes and adherence to screening guidelines. Complementary approaches of screening and lifestyle modification will likely provide the greatest reduction of colorectal cancer. Cancer Prev Res; 5(1); 138–45. ©2011 AACR.
Data from Breast Cancer Cell Apoptosis with Phytoestrogens Is Dependent on an Estrogen-Deprived State
Authors: Obiorah Ifeyinwa E. , Fan Ping , Jordan V. Craig
Published: March 2024

Abstract
Phytoestrogens have been investigated as natural alternatives to hormone replacement therapy and their potential as chemopreventive agents. We investigated the effects of equol, genistein, and coumestrol on cell growth in fully estrogenized MCF7 cells, simulating the perimenopausal state, and long-term estrogen-deprived MCF7:5C cells, which simulate the postmenopausal state of a woman after years of estrogen deprivation, and compared the effects with that of steroidal estrogens: 17β estradiol (E2) and equilin present in conjugated equine estrogen. Steroidal and phytoestrogens induce proliferation of MCF7 cells at physiologic concentrations but inhibit the growth and induce apoptosis of MCF7:5C cells. Although steroidal and phytoestrogens induce estrogen-responsive genes, their antiproliferative and apoptotic effects are mediated through the estrogen receptor. Knockdown of ERα using siRNA blocks all estrogen-induced apoptosis and growth inhibition. Phytoestrogens induce endoplasmic reticulum stress and inflammatory response stress–related genes in a comparable manner as the steroidal estrogens. Inhibition of inflammation using dexamethasone blocked both steroidal- and phytoestrogen-induced apoptosis and growth inhibition as well as their ability to induce apoptotic genes. Together, this suggests that phytoestrogens can potentially be used as chemopreventive agents in older postmenopausal women but caution should be exercised when used in conjunction with steroidal anti-inflammatory agents due to their antiapoptotic effects. Cancer Prev Res; 7(9); 939–49. ©2014 AACR.
Data from (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38
Authors: Lim Do Young , Lee Mee-Hyun , Shin Seung Ho , Chen Hanyoung , Ryu Joohyun , Shan Lei , Li Honglin , Bode Ann M. , Zhang Wei-Dong , Dong Zigang
Published: March 2024

Abstract
For decades, skin cancer incidence has increased, mainly because of oncogenic signaling pathways activated by solar ultraviolet (UV) irradiation (i.e., sun exposure). Solar UV induces multiple signaling pathways that are critical in the development of skin cancer, and therefore the development of compounds capable of targeting multiple molecules for chemoprevention of skin carcinogenesis is urgently needed. Herein, we examined the chemopreventive effects and the molecular mechanism of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 Cl41 cells without toxicity. PI3K, ERK1/2, and p38 kinase activities were suppressed by direct binding with HOEC in vitro. Our in silico docking data showed that HOEC binds at the ATP-binding site of each kinase. The inhibition of solar UV-induced PI3K, ERK1/2, and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP1 and NF-κB transactivation in JB6 cells. Furthermore, topical application of HOEC reduced skin cancer incidence and tumor volume in SKH-1 hairless mice chronically exposed to solar UV. In summary, our results show that HOEC exerts inhibitory effects on multiple kinase targets and their downstream pathways activated by solar UV in vitro and in vivo. These findings suggest that HOEC is a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure. Cancer Prev Res; 7(8); 856–65. ©2014 AACR.