bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accelerated Bone Resorption, Due to Dietary Calcium Deficiency, Promotes Breast Cancer Tumor Growth in Bone
Authors: Zheng Yu , Zhou Hong , Modzelewski James R.K. , Kalak Robert , Blair Julie M. , Seibel Markus J. , Dunstan Colin R. 
Published: October 2007

Abstract
The skeleton is a major site of breast cancer metastases. High bone turnover increases risk of disease progression and death. However, there is no direct evidence that high bone turnover is causally associated with the establishment and progression of metastases. In this study, we investigate the effects of high bone turnover in a model of breast cancer growth in bone. Female nude mice commenced a diet containing normal (0.6%; ‘Normal-Ca’) or low (0.1%; ‘Low-Ca’) calcium content. Mice were concurrently treated with vehicle or osteoprotegerin (1 mg/kg/d s.c; n = 16 per group). Three days later (day 0), 50,000 Tx-SA cells (variant of MDA-MB-231 cells) were implanted by intratibial injection. On day 0, mice receiving Low-Ca had increased serum parathyroid hormone (PTH) and tartrate-resistant acid phosphatase 5b levels, indicating secondary hyperparathyroidism and high bone turnover, which was maintained until day 17. Osteoprotegerin increased serum PTH but profoundly reduced bone resorption. On day 17, in mice receiving Low-Ca alone, lytic lesion area, tumor area, and cancer cell proliferation increased by 43%, 24%, and 24%, respectively, compared with mice receiving Normal Ca (P &lt; 0.01). Osteoprotegerin treatment completely inhibited lytic lesions, reduced tumor area, decreased cancer cell proliferation, and increased cancer cell apoptosis. Increased bone turnover, due to dietary calcium deficiency, promotes tumor growth in bone, independent of the action of PTH. Breast cancer patients frequently have low dietary calcium intake and high bone turnover. Treatment to correct calcium insufficiency and/or treatment with antiresorptive agents, such as osteoprotegerin, may be of benefit in the adjuvant as well as palliative setting. [Cancer Res 2007;67(17):9542–8]
β-Catenin Regulates Multiple Steps of RNA Metabolism as Revealed by the RNA Aptamer in Colon Cancer Cells
Authors: Lee Hee Kyu , Kwak Ho Yoon , Hur Jung , Kim In Ae , Yang Ji Sun , Park Min Woo , Yu Jaehoon , Jeong Sunjoo 
Published: October 2007

Abstract
Nuclear β-catenin forms a transcription complex with TCF-4, which is implicated in colon cancer development and progression. Recently, we and others have shown that β-catenin could be a regulator of RNA splicing and it also stabilizes the cyclooxygenase-2 (COX-2) mRNA. Here, we further explored the role of β-catenin in the RNA metabolism in colon cancer cells. To specifically modulate the subcellular functions of β-catenin, we expressed the RNA aptamer in the form of RNA intramers with unique cellular localizations. The nucleus-expressed RNA intramer proved to be effective in reducing the protein-protein interaction between β-catenin and TCF-4, thus shown to be a specific regulator of β-catenin–activated transcription. It could also regulate the alternative splicing of E1A minigene in diverse colon cancer cell lines. In addition, we tested whether β-catenin could stabilize any other mRNAs and found that cyclin D1 mRNA was also bound and stabilized by β-catenin. Significantly, the cytoplasm-expressed RNA intramer reverted the β-catenin–induced COX-2 and cyclin D1 mRNA stabilization. We show here that β-catenin regulated multiple steps of RNA metabolism in colon cancer cells and might be the protein factor coordinating RNA metabolism. We suggest that the RNA intramers could provide useful ways for inhibiting β-catenin–mediated transcription and RNA metabolism, which might further enhance the antitumorigenic effects of these molecules in colon cancer cells. [Cancer Res 2007;67(19):9315–20]
Cisplatin Depletes TREX2 and Causes Robertsonian Translocations as Seen in TREX2 Knockout Cells
Authors: Chen Ming-Jiu , Dumitrache Lavinia C. , Wangsa Danny , Ma Sheng-Mei , Padilla-Nash Hesed , Ried Thomas , Hasty Paul 
Published: October 2007

Abstract
Cisplatin, an anticancer drug, forms DNA interstrand cross-links (ICL) that interfere with replication, whereas TREX2 is a 3′→5′ exonuclease that removes 3′ mismatched nucleotides and promotes cellular proliferation. Here, we show that TREX2 is depleted in human cells derived from cancer after exposure to cisplatin but not other genotoxins including another cross-linking agent, mitomycin C (MMC), indicating a potential role for TREX2 depletion in cisplatin-induced cytotoxicity. To better understand TREX2 cellular function, we deleted TREX2 in mouse embryonic stem (ES) cells by gene targeting and find these cells exhibit reduced proliferation and gross chromosomal rearrangements including Robertsonian translocations (RbT). Quite interestingly, ES cells exposed to cisplatin also exhibit RbTs. By contrast, RbTs are not observed for ES cells exposed to MMC, indicating that RbTs are not caused by ICLs but instead TREX2 depletion by either cisplatin exposure or mutation. Taken together, our results show that cisplatin depletes TREX2 and causes genomic instability that is similarly observed in TREX2-mutant cells. Thus, cisplatin has two potential cytotoxic activities: (a) the generation of ICLs and (b) the depletion of TREX2. [Cancer Res 2007;67(19):9077–83]
c-Fos as a Proapoptotic Agent in TRAIL-Induced Apoptosis in Prostate Cancer Cells
Authors: Zhang Xiaoping , Zhang Liang , Yang Hongmei , Huang Xu , Otu Hasan , Libermann Towia A. , DeWolf William C. , Khosravi-Far Roya , Olumi Aria F. 
Published: October 2007

Abstract
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)/Apo-2L promotes apoptosis in cancer cells while sparing normal cells. Although many cancers are sensitive to TRAIL-induced apoptosis, some evade the proapoptotic effects of TRAIL. Therefore, differentiating molecular mechanisms that distinguish between TRAIL-sensitive and TRAIL-resistant tumors are essential for effective cancer therapies. Here, we show that c-Fos functions as a proapoptotic agent by repressing the antiapoptotic molecule c-FLIP(L). c-Fos binds the c-FLIP(L) promoter, represses its transcriptional activity, and reduces c-FLIP(L) mRNA and protein levels. Therefore, c-Fos is a key regulator of c-FLIP(L), and activation of c-Fos determines whether a cancer cell will undergo cell death after TRAIL treatment. Strategies to activate c-Fos or inhibit c-FLIP(L) may potentiate TRAIL-based proapoptotic therapies. [Cancer Res 2007;67(19):9425–34]
A Placenta-Specific Gene Ectopically Activated in Many Human Cancers Is Essentially Involved in Malignant Cell Processes
Authors: Koslowski Michael , Sahin Ugur , Mitnacht-Kraus Rita , Seitz Gerhard , Huber Christoph , Türeci Özlem 
Published: October 2007

Abstract
The identification and functional characterization of tumor-specific genes is a prerequisite for the development of targeted cancer therapies. Using an integrated data mining and experimental validation approach for the discovery of new targets for antibody therapy of cancer, we identified PLAC1. PLAC1 is a placenta-specific gene with no detectable expression in any other normal human tissue. However, it is frequently aberrantly activated and highly expressed in a variety of tumor types, in particular breast cancer. RNAi-mediated silencing of PLAC1 in MCF-7 and BT-549 breast cancer cells profoundly impairs motility, migration, and invasion and induces a G1-S cell cycle block with nearly complete abrogation of proliferation. Knockdown of PLAC1 is associated with decreased expression of cyclin D1 and reduced phosphorylation of AKT kinase. Moreover, PLAC1 is localized on the surface of cancer cells and is accessible for antibodies which antagonize biological functions of this molecule. These features, in summary, make PLAC1 an attractive candidate for targeted immunotherapeutic approaches. [Cancer Res 2007;67(19):9528–34]
Cell Cycle–Dependent and Schedule-Dependent Antitumor Effects of Sorafenib Combined with Radiation
Authors: Plastaras John P. , Kim Seok-Hyun , Liu Yingqiu Y. , Dicker David T. , Dorsey Jay F. , McDonough James , Cerniglia George , Rajendran Ramji R. , Gupta Anjali , Rustgi Anil K. , Diehl J. Alan , Smith Charles D. , Flaherty Keith T. , El-Deiry Wafik S. 
Published: October 2007

Abstract
The antineoplastic drug sorafenib (BAY 43-9006) is a multikinase inhibitor that targets the serine-threonine kinase B-Raf as well as several tyrosine kinases. Given the numerous molecular targets of sorafenib, there are several potential anticancer mechanisms of action, including induction of apoptosis, cytostasis, and antiangiogenesis. We observed that sorafenib has broad activity in viability assays in several human tumor cell lines but selectively induces apoptosis in only some lines. Sorafenib was found to decrease Mcl-1 levels in most cell lines tested, but this decrease did not correlate with apoptotic sensitivity. Sorafenib slows cell cycle progression and prevents irradiated cells from reaching and accumulating at G2-M. In synchronized cells, sorafenib causes a reversible G1 delay, which is associated with decreased levels of cyclin D1, Rb, and phosphorylation of Rb. Although sorafenib does not affect intrinsic radiosensitivity using in vitro colony formation assays, it significantly reduces colony size. In HCT116 xenograft tumor growth delay experiments in mice, sorafenib alters radiation response in a schedule-dependent manner. Radiation treatment followed sequentially by sorafenib was found to be associated with the greatest tumor growth delay. This study establishes a foundation for clinical testing of sequential fractionated radiation followed by sorafenib in gastrointestinal and other malignancies. [Cancer Res 2007;67(19):9443–54]
The Cooked Meat–Derived Genotoxic Carcinogen 2-Amino-3-Methylimidazo[4,5-b]Pyridine Has Potent Hormone-Like Activity: Mechanistic Support for a Role in Breast Cancer
Authors: Lauber Sandra N. , Gooderham Nigel J. 
Published: October 2007

Abstract
The cooked meat–derived heterocyclic amine 2-amino-3-methylimidazo[4,5-b]pyridine (PhIP) is activated by CYP1A2 to the N-hydroxy metabolite, then esterified by acetyl transferase and sulfur transferase into unstable DNA-reactive products that can lead to mutation. The genotoxicity of PhIP has been implicated in its carcinogenicity. Yet, CYP1A2-null mice are still prone to PhIP-mediated cancer, inferring that alternative mechanisms must be operative in tumor induction. PhIP induces tumors of the breast, prostate, and colon in rats and lymphoma in mice. This profile of carcinogenicity is indicative of hormonal involvement. We recently reported that PhIP has potent estrogenic activity inducing transcription of estrogen (E2)-regulated genes, proliferation of E2-dependent cells, up-regulation of progesterone receptor, and stimulation of mitogen-activated protein kinase signaling. In this report, we show for the first time that PhIP at doses as low as of 10−11 mol/L has direct effects on a rat pituitary lactotroph model (GH3 cells) and is able to induce cell proliferation and the synthesis and secretion of prolactin. This PhIP-induced pituitary cell proliferation and synthesis and secretion of prolactin can be attenuated by an estrogen receptor (ER) inhibitor, implying that PhIP effects on lactotroph responses are ERα mediated. In view of the strong association between estrogen, progesterone, prolactin, and breast cancer, the PhIP repertoire of hormone-like activities provides further mechanistic support for the tissue-specific carcinogenicity of the chemical. Furthermore, the recent epidemiology studies that report an association between consumption of cooked red meat and premenopausal and postmenopausal human breast cancer are consonant with these observations. [Cancer Res 2007;67(19):9597–602]
Inhibition of the Proteasome Activity by Gallium(III) Complexes Contributes to Their Anti–Prostate Tumor Effects
Authors: Chen Di , Frezza Michael , Shakya Rajendra , Cui Qiuzhi Cindy , Milacic Vesna , Verani Claudio N. , Dou Q. Ping 
Published: October 2007

AbstractThe investigation of metal-based complexes with potential antitumor activity has been of paramount importance in recent years due to the successful use of cisplatin against various cancers. Gallium(III) and subsequently developed gallium(III)-containing complexes have shown promising antineoplastic effects when tested in a host of malignancies, specifically in lymphomas and bladder cancer. However, the molecular mechanism responsible for their anticancer effect is yet to be fully understood. We report here for the first time that the proteasome is a molecular target for gallium complexes in a variety of prostate cancer cell lines and in human prostate cancer xenografts. We tested five gallium complexes (1–5) in which the gallium ion is bound to an NN′O asymmetrical ligand containing pyridine and substituted phenolate moieties in a 1:2 (M/L) ratio. We found that complex 5 showed superior proteasome inhibitory activity against both 26S proteasome (IC50, 17 μmol/L) and purified 20S (IC50, 16 μmol/L) proteasome. Consistently, this effect was associated with apoptosis induction in prostate cancer cells. Additionally, complex 5 was able to exert the same effect in vivo by inhibiting growth of PC-3 xenografts in mice (66%), which was associated with proteasome inhibition and apoptosis induction. Our results strongly suggest that gallium complexes, acting as potent proteasome inhibitors, have a great potential to be developed into novel anticancer drugs. [Cancer Res 2007;67(19):9258–65]
Insulin Receptor Substrate-1 Is an Important Mediator of Ovarian Cancer Cell Growth Suppression by All-trans Retinoic Acid
Authors: Ravikumar Sharada , Perez-Liz Georgina , Del Vale Luis , Soprano Dianne Robert , Soprano Kenneth J. 
Published: October 2007

Abstract
There is a need to identify more effective drugs for the treatment of ovarian cancer as it is the leading cause of death among gynecologic tumors. All-trans retinoic acid (ATRA), a natural retinoid, arrests the growth of CA-OV3 ovarian carcinoma cells in G0-G1. Because the insulin-like growth factor-I receptor has been implicated in the proliferation of various tumors, we investigated its potential role in the suppression of ovarian cancer cell growth by ATRA. Our studies revealed that insulin receptor substrate-1 (IRS-1) protein levels decrease in CA-OV3 cells on ATRA treatment, whereas no differences in IRS-1 levels were seen in the ATRA-resistant SK-OV3 cells. Moreover, CA-OV3 clones overexpressing IRS-1 were growth inhibited less by ATRA, whereas SK-OV3 clones in which levels of IRS-1 were reduced by expression of antisense IRS-1 became sensitive to growth inhibition by ATRA treatment. Studies to determine the mechanism by which ATRA reduced IRS-1 expression showed that ATRA altered steady-state levels of IRS-1 mRNA and the stability of IRS-1 protein. Finally, the role of IRS-1 as a potential molecular target of ATRA in ovarian tumors was assessed by immunohistochemistry in an ovarian cancer tissue array. Compared with normal ovary, the majority of malignant epithelial ovarian tumors overexpressed IRS-1. Thus, there seems to be a correlation between IRS-1 expression and malignancy in ovarian tumors. Our results suggest that IRS-1 is in fact an important growth-regulatory molecule that can be a potential effective target for chemotherapeutic intervention with growth-suppressive agents, including retinoids. [Cancer Res 2007;67(19):9266–75]
Association of Wwox with ErbB4 in Breast Cancer
Authors: Aqeilan Rami I. , Donati Valentina , Gaudio Eugenio , Nicoloso Milena S. , Sundvall Maria , Korhonen Anna , Lundin Johan , Isola Jorma , Sudol Marius , Joensuu Heikki , Croce Carlo M. , Elenius Klaus 
Published: October 2007

Abstract
WWOX, WW domain-containing oxidoreductase, is a tumor suppressor that is altered in many human cancers, including breast cancer. Wwox interacts with the ErbB4 receptor, reduces nuclear translocation of the cleaved intracellular domain of ErbB4, and inhibits its transactivation function mediated through Yes-associated protein. Here, we assessed the clinical significance of the Wwox-ErbB4 association. We determined Wwox protein expression by immunohistochemistry in a series of 556 breast cancers. Wwox expression was absent in 36% of the cancers, and loss of Wwox expression was associated with unfavorable outcome (P = 0.02). Membranous location of ErbB4 was associated with favorable survival compared with women whose cancer lacked such ErbB4 expression (P = 0.02). Wwox expression was strongly associated with membranous ErbB4 localization (P = 0.0003) and with overall ErbB4 expression (P = 0.0002). Coexpression of membranous ErbB4 and Wwox was associated with favorable outcome compared with cases with membranous ErbB4 and no Wwox immunoreactivity (P = 0.002). In vitro, Wwox associated with the two ErbB4 isoforms, JM-a CYT-1 and JM-a CYT-2, expressed in breast cancer. Moreover, expression of Wwox both in vitro and in vivo led to accumulation of total full-length membrane-associated ErbB4. These results suggest that expression of Wwox is associated with ErbB4 expression and that their coexpression has prognostic significance in breast cancer. [Cancer Res 2007;67(19):9330–6]
Prolonged Exposure to Reduced Levels of Androgen Accelerates Prostate Cancer Progression in Nkx3.1; Pten Mutant Mice
Authors: Banach-Petrosky Whitney , Jessen Walter J. , Ouyang Xuesong , Gao Hui , Rao Jayashree , Quinn John , Aronow Bruce J. , Abate-Shen Cory 
Published: October 2007

Abstract
In this report, we have investigated the relationship between androgen levels and prostate tumorigenesis in Nkx3.1; Pten mutant mice, a genetically engineered mouse model of human prostate cancer. By experimentally manipulating serum levels of testosterone in these mice for an extended period (i.e., 7 months), we have found that prolonged exposure of Nkx3.1; Pten mutant mice to androgen levels that are 10-fold lower than normal (the “Low-T” group) resulted in a marked acceleration of prostate tumorigenesis compared with those exposed to androgen levels within the reference range (the “Normal-T” group). We found that prostate tumors from the Low-T mutant mice share a similar gene expression profile as androgen-independent prostate tumors from these mutant mice, which includes the deregulated expression of several genes that are up-regulated in human hormone-refractory prostate cancer, such as Vav3 and Runx1. We propose that exposure to reduced androgens may promote prostate tumorigenesis by selecting for molecular events that promote more aggressive, hormone-refractory tumors. [Cancer Res 2007;67(19):9089–96]
The AA Genotype of the Regulatory BCL2 Promoter Polymorphism (−938C&gt;A) Is Associated with a Favorable Outcome in Lymph Node–Negative Invasive Breast Cancer Patients
Authors: Bachmann Hagen S. , Otterbach Friedrich , Callies Rainer , Nückel Holger , Bau Maja , Schmid Kurt W. , Siffert Winfried , Kimmig Rainer 
Published: October 2007

Abstract
Purpose: Expression of the antiapoptotic and antiproliferative protein Bcl-2 has been repeatedly shown to be associated with better clinical outcome in breast cancer. We recently showed a novel regulatory (−938C&gt;A) single-nucleotide polymorphism (SNP) in the inhibitory P2 BCL2 gene promoter generating significantly different BCL2 promoter activities.
Experimental Design: Paraffin-embedded neoplastic and nonneoplastic tissues from 274 patients (161 still alive after a follow-up period of at least 80 months) with primary unilateral invasive breast carcinoma were investigated. Bcl-2 expression of tumor cells was shown by immunohistochemistry; nonneoplastic tissues were used for genotyping. Both the Bcl-2 expression and the (−938C&gt;A) genotypes were correlated with the patients' survival.
Results: Kaplan-Meier curves revealed a significant association of the AA genotype with increased survival (P = 0.030) in lymph node–negative breast cancer patients, whereas no genotype effect could be observed in lymph node–positive cases. Ten-year survival rates were 88.6% for the AA genotype, 78.4% for the AC genotype, and 65.8% for the CC genotype. Multivariable Cox regression identified the BCL2 (−938CC) genotype as an independent prognostic factor for cancer-related death in lymph node–negative breast carcinoma patients (hazard ratio, 3.59; P = 0.032). Immunohistochemical Bcl-2 expression was significantly associated with the clinical outcome of lymph node–positive but not of lymph node–negative breast cancer patients. In lymph node–negative cases, the (−938C&gt;A) SNP was both significantly related with the immunohistochemically determined level of Bcl-2 expression (P = 0.044) and the survival of patients with Bcl-2–expressing carcinomas (P = 0.006).
Conclusions: These results suggest the (−938C&gt;A) polymorphism as a survival prognosticator as well as indicator of a high-risk group within patients with lymph node–negative breast cancer.
Preclinical Testing of Clinically Applicable Strategies for Overcoming Trastuzumab Resistance Caused by PTEN Deficiency
Authors: Lu Chien-Hsing , Wyszomierski Shannon L. , Tseng Ling-Ming , Sun Meng-Hong , Lan Keng-Hsueh , Neal Christopher L. , Mills Gordon B. , Hortobagyi Gabriel N. , Esteva Francisco J. , Yu Dihua 
Published: October 2007

Abstract
Purpose: We have previously shown that PTEN loss confers trastuzumab resistance in ErbB2-overexpressing breast cancer using cell culture, xenograft models, and patient samples. This is a critical clinical problem because trastuzumab is used in a variety of therapeutic regimens, and at the current time, there are no established clinical strategies to overcome trastuzumab resistance. Here, we did preclinical studies on the efficacy of clinically applicable inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway to restore trastuzumab sensitivity to PTEN-deficient cells.
Experimental Design: Cell culture and xenograft models were used to test a panel of clinically applicable, small-molecule inhibitors of the Akt/mTOR signal transduction pathway, a critical pathway downstream of ErbB2, and identify compounds with the ability to restore trastuzumab sensitivity to PTEN-deficient cells.
Results: When trastuzumab was combined with the Akt inhibitor triciribine, breast cancer cell growth was inhibited and apoptosis was induced. In a xenograft model, combination therapy with trastuzumab and triciribine dramatically inhibited tumor growth. The combination of trastuzumab and the mTOR inhibitor RAD001 also slowed breast cancer cell growth in vitro and in vivo.
Conclusions: Combining trastuzumab with inhibitors of the Akt/mTOR pathway is a clinically applicable strategy and combinations of trastuzumab with triciribine or RAD001 are promising regimens for rescue of trastuzumab resistance caused by PTEN loss.