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Liver X receptors (LXRs) are nuclear transcription factors important in the regulation of cholesterol transport, and glucose and fatty acid metabolism. The antiproliferative role of LXRs has been studied in a variety of malignancies and may represent a therapeutic opportunity in cancers lacking targeted therapies, such as triple‐negative breast cancer. In this study, we investigated the impact of LXR agonists alone and in combination with carboplatin in preclinical models of breast cancer. In vitro experiments revealed a dose‐dependent decrease in tumor cell proliferation in estrogen receptor‐positive breast cancer cells, whereas LXR activation in vivo resulted in an increased growth inhibitory effect in a basal‐like breast cancer model (in combination with carboplatin). Functional proteomic analysis identified differences in protein expression between responding and nonresponding models related to Akt activity, cell‐cycle progression, and DNA repair. Furthermore, pathway analysis suggested that the LXR agonist in combination with carboplatin inhibits the activity of targets of E2F transcription factors and affects cholesterol homeostasis in basal‐like breast cancer.

The androgen receptor (AR) and the phosphoinositide 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) signaling are two of the major proliferative pathways in a number of tissues and are the main therapeutic targets in various disorders, including prostate cancer (PCa). Previous work has shown that there is reciprocal feedback regulation of PI3K and AR signaling in PCa, suggesting that cotargeting both pathways may enhance therapeutic efficacy. Here we show that proteins encoded by two androgen-regulated genes, kallikrein related peptidase 4 (KLK4) and promyelocytic leukemia zinc finger (PLZF), integrate optimal functioning of AR and mTOR signaling in PCa cells. KLK4 interacts with PLZF and decreases its stability. PLZF in turn interacts with AR and inhibits its function as a transcription factor. PLZF also activates expression of regulated in development and DNA damage responses 1, an inhibitor of mTORC1. Thus, a unique molecular switch is generated that regulates both AR and PI3K signaling. Consistently, KLK4 knockdown results in a significant decline in PCa cell proliferation in vitro and in vivo, decreases anchorage-independent growth, induces apoptosis, and dramatically sensitizes PCa cells to apoptosis-inducing agents. Furthermore, in vivo nanoliposomal KLK4 siRNA delivery in mice bearing PCa tumors results in profound remission. These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy.

Background Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) may be used to depict tumour vascular structure and for therapy response assessment in various tumour sites. The purpose of the current work is to examine whether ultra-early changes in tumour physiology following cytotoxic treatment with doxorubicin and liver X receptor (LXR) agonist GW3965 are detectable by DCE-MRI. Methods 36 female, athymic nude foxn1nu mice with bilaterally implanted breast cancer xenografts (17 with ER-positive HBCx34, 19 with triple-negative HBCx39) were randomised in the following treatment groups; control, GW3965 (40 mg/kg p.o.), doxorubicin (8 mg/kg i.v.) and a combination therapy of GW3965 and doxorubicin. DCE-MRI (3D FLASH on a 7 T preclinical scanner) was performed at baseline and one and six days after onset of treatment. Wash-in (30 s p.i.) and wash-out (300 s p.i.) enhancement were quantified from dynamic uptake curves, before voxel-by-voxel fitting to the pharmacokinetic Tofts model and generation of maps for the resulting parameters K trans , ν e and ν B . Treatment effect was evaluated by univariate repeated measures mixed-effects maximum likelihood regression models applied to median tumour data. Results We found no effects of any treatment 24 h post treatment. After 6 days, doxorubicin given as both mono- and combination therapy gave significant increases of ~ 30% in wash-in enhancement ( p  < 0.011) and K trans ( p  < 0.017), and 40–50% in ν B ( p  < 0.024) for HBCx34, but not for HBCx39. No effects of GW3965 were observed at any time ( p  > 0.1). Conclusions Twenty-four h after onset of treatment was too early to evaluate treatment effects by DCE-MRI. Early enhancement and K trans were approximately equally sensitive metrics to capture treatment effects six days pt. Pharmacokinetic modelling however allowed us to attribute the observed effect to changes in tumour perfusion rather than increased retention.

The six transmembrane protein of prostate 2 ( STAMP2) is an androgen‐regulated gene whose mRNA expression is increased in prostate cancer (PCa). Here, we show that STAMP2 protein expression is increased in human PCa compared with benign prostate that is also correlated with tumor grade and treatment response. We also show that STAMP2 significantly increased reactive oxygen species (ROS) in PCa cells through its iron reductase activity which also depleted NADPH levels. Knockdown of STAMP2 expression in PCa cells inhibited proliferation, colony formation, and anchorage‐independent growth, and significantly increased apoptosis. Furthermore, STAMP2 effects were, at least in part, mediated by activating transcription factor 4 (ATF4), whose expression is regulated by ROS. Consistent with in vitro findings, silencing STAMP2 significantly inhibited PCa xenograft growth in mice. Finally, therapeutic silencing of STAMP2 by systemically administered nanoliposomal siRNA profoundly inhibited tumor growth in two established preclinical PCa models in mice. These data suggest that STAMP2 is required for PCa progression and thus may serve as a novel therapeutic target. Synopsis The androgen‐regulated transmembrane protein STAMP2 is shown to be a critical factor in prostate cancer progression and a possible therapeutic target. STAMP2 regulates cell proliferation by increasing ROS, which in turn activate ATF4 expression. During prostate cancer progression, STAMP2 expression is deregulated and correlated with tumor grade and response to treatment. STAMP2 knockdown inhibits cell proliferation, colony formation, and anchorage‐independent growth, while significantly increasing apoptosis. STAMP2 significantly increases ROS through its iron reductase activity and depletes NADPH levels resulting in ATF4 expression. Therapeutic STAMP2 silencing by systemically administered nanoliposomal siRNA profoundly inhibits tumor growth in preclinical prostate cancer models suggesting that STAMP2 may serve as a novel therapeutic target. Graphical Abstract The androgen‐regulated transmembrane protein STAMP2 is shown to be a critical factor in prostate cancer progression and a possible therapeutic target. STAMP2 regulates cell proliferation by increasing ROS, which in turn activate ATF4 expression.

Malignant melanoma is an exceptionally aggressive, drug-resistant and heterogeneous cancer. Recently it has been shown that melanoma cells with high clonogenic and tumourigenic abilities are common, but markers distinguishing such cells from cells lacking these abilities have not been identified. There is therefore no definite evidence that an exclusive cell subpopulation, i.e. cancer stem cells (CSC), exists in malignant melanoma. Rather, it is suggested that multiple cell populations are implicated in initiation and progression of the disease, making it of importance to identify subpopulations with elevated aggressive properties. In several other cancer forms, Aldehyde Dehydrogenase (ALDH), which plays a role in stem cell biology and resistance, is a valuable functional marker for identification of cells that show enhanced aggressiveness and drug-resistance. Furthermore, the presence of ALDH(+) cells is linked to poor clinical prognosis in these cancers. By analyzing cell cultures, xenografts and patient biopsies, we showed that aggressive melanoma harboured a large, distinguishable ALDH(+) subpopulation. In vivo, ALDH(+) cells gave rise to ALDH(-) cells, while the opposite conversion was rare, indicating a higher abilities of ALDH(+) cells to reestablish tumour heterogeneity with respect to the ALDH phenotype. However, both ALDH(+) and ALDH(-) cells demonstrated similarly high abilities for clone formation in vitro and tumour initiation in vivo. Furthermore, both subpopulations showed similar sensitivity to the anti-melanoma drugs, dacarbazine and lexatumumab. These findings suggest that ALDH does not distinguish tumour-initiating and/or therapy-resistant cells, implying that the ALDH phenotype is not associated with more-aggressive subpopulations in malignant melanoma, and arguing against ALDH as a \"universal\" marker. Besides, it was shown that the ability to reestablish tumour heterogeneity is not necessarily linked to the more aggressive phenotype.

Intratumor heterogeneity caused by genetic, phenotypic or functional differences between cancer cell subpopulations is a considerable clinical challenge. Understanding subpopulation dynamics is therefore central for both optimization of existing therapy and for development of new treatment. The aim of this study was to isolate subpopulations from a primary tumor and by comparing molecular characteristics of these subpopulations, find explanations to their differing tumorigenicity. Cell subpopulations from two patient derived in vivo models of primary breast cancer, ER+ and ER-, were identified. EpCAM+ cells from the ER+ model gave rise to tumors independently of stroma cell support. The tumorigenic fraction was further divided based on SSEA-4 and CD24 expression. Both markers were expressed in ER+ breast cancer biopsies. FAC-sorted cells based on EpCAM, SSEA-4 and CD24 expression were subsequently tested for differences in functionality by in vivo tumorigenicity assay. Three out of four subpopulations of cells were tumorigenic and showed variable ability to recapitulate the marker expression of the original tumor. Whole genome expression analysis of the sorted populations disclosed high similarity in the transcriptional profiles between the tumorigenic populations. Comparing the non-tumorigenic vs the tumorigenic populations, 44 transcripts were, however, significantly differentially expressed. A subset of these, 26 identified and named genes, highly expressed in the non-tumorigenic population, predicted longer overall survival (N = 737, p<0.0001) and distant metastasis free survival (DMFS) (N = 1379, p<0.0001) when performing Kaplan-Meier survival analysis using the GOBO online database. The 26 gene set correlated with longer DMFS in multiple breast cancer subgroups. Copy number profiling revealed no aberrations that could explain the observed differences in tumorigenicity. This study emphasizes the functional variability among cell populations that are otherwise genomically similar, and that the risk of breast cancer recurrence can only be eliminated if the tumorigenic abilities in multiple cancer cell subpopulations are inhibited.

Background The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials. Methods Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models. Results Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth. Conclusions Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo . The results encourage implementation of vorinostat into CRT in LARC trials.

Background Mitomycin C is a chemotherapeutic agent used in the treatment of peritoneal surface malignancies, administered as hyperthermic intraperitoneal chemotherapy after cytoreductive surgery. Pharmacokinetic studies have been based on analyses of blood, urine and abdominal perfusate, but actual tissue concentrations of the drug have never been determined. Microdialysis is an established method for continuous monitoring of low-molecular substances in tissues, and in the present study microdialysis of mitomycin C was studied in vitro and in vivo. Methods Using in vitro microdialysis, relative recovery was determined when varying drug concentration, temperature and perfusion flow rate. In vivo microdialysis was performed in rats to verify long-term stability of relative recovery in four compartments (vein, peritoneum, extraperitoneal space and hind leg muscle). Subsequently, intravenous and intraperitoneal bolus infusion experiments were performed and pharmacokinetic parameters were calculated. Results In vitro, compatibility of mitomycin C and microdialysis equipment was demonstrated, and relative recovery was stable over an adequate concentration range, moderately increased by raising medium temperature and increased when flow rate was reduced, all according to theory. In vivo, stable relative recovery was observed over seven hours. Mitomycin C exhibited fast and even distribution in rat tissues, and equal bioavailability was achieved by intravenous and intraperitoneal infusion. The half-life of mitomycin C calculated after intravenous infusion was 40 minutes. Conclusions Mitomycin C concentration can be reliable monitored in vivo using microdialysis, suggesting that this technique can be used in pharmacokinetic studies of this drug during hyperthermic intraperitoneal chemotherapy.

Purpose Non-invasive response monitoring can potentially be used to guide therapy selection for breast cancer patients. We employed dynamic 2-deoxy-2-[ 18 F]fluoro-D-glucose positron emission tomography ([ 18 F]FDG PET) to evaluate changes in three breast cancer xenograft lines in mice following three chemotherapy regimens. Procedures Sixty-six athymic nude mice bearing bilateral breast cancer xenografts (two basal-like and one luminal-like subtype) underwent three 60 min [ 18 F]FDG PET scans. Scans were performed prior to and 3 and 10 days after treatment with doxorubicin, paclitaxel, or carboplatin. Tumor growth was monitored in parallel. A pharmacokinetic compartmental model was fitted to the tumor uptake curves, providing estimates of transfer rates between the vascular, non-metabolized, and metabolized compartments. Early and late standardized uptake values (SUV E and SUV L , respectively); the rate constants k 1 , k 2 , and k 3 , and the intravascular fraction v B were estimated. Changes in tumor volume were used as a response measure. Multivariate partial least-squares regression (PLSR) was used to assess if PET parameters could model tumor response and to identify PET parameters with the largest impact on response. Results Treatment responders had significantly larger perfusion-related parameters ( k 1 and k 2 ) and lower metabolism-related parameter ( k 3 ) than non-responders 10 days after the start of treatment. These findings were further supported by the PLSR analysis, which showed that k 1 and k 2 at day 10 and changes in k 3 explained most of the variability in response to therapy, whereas SUV L and particularly SUV E were of lesser importance. Conclusions Overall, rate parameters related to both tumor perfusion and metabolism were associated with tumor response. Conventional metrics of [ 18 F]FDG uptake such as SUV E and SUV L apparently had little relation to tumor response, thus necessitating full dynamic scanning and pharmacokinetic analysis for optimal evaluation of chemotherapy-induced changes in breast cancers.

Non-invasive response monitoring can potentially be used to guide therapy selection for breast cancer patients. We employed dynamic 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG PET) to evaluate changes in three breast cancer xenograft lines in mice following three chemotherapy regimens.PURPOSENon-invasive response monitoring can potentially be used to guide therapy selection for breast cancer patients. We employed dynamic 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG PET) to evaluate changes in three breast cancer xenograft lines in mice following three chemotherapy regimens.Sixty-six athymic nude mice bearing bilateral breast cancer xenografts (two basal-like and one luminal-like subtype) underwent three 60 min [18F]FDG PET scans. Scans were performed prior to and 3 and 10 days after treatment with doxorubicin, paclitaxel, or carboplatin. Tumor growth was monitored in parallel. A pharmacokinetic compartmental model was fitted to the tumor uptake curves, providing estimates of transfer rates between the vascular, non-metabolized, and metabolized compartments. Early and late standardized uptake values (SUVE and SUVL, respectively); the rate constants k 1, k 2, and k 3, and the intravascular fraction v B were estimated. Changes in tumor volume were used as a response measure. Multivariate partial least-squares regression (PLSR) was used to assess if PET parameters could model tumor response and to identify PET parameters with the largest impact on response.PROCEDURESSixty-six athymic nude mice bearing bilateral breast cancer xenografts (two basal-like and one luminal-like subtype) underwent three 60 min [18F]FDG PET scans. Scans were performed prior to and 3 and 10 days after treatment with doxorubicin, paclitaxel, or carboplatin. Tumor growth was monitored in parallel. A pharmacokinetic compartmental model was fitted to the tumor uptake curves, providing estimates of transfer rates between the vascular, non-metabolized, and metabolized compartments. Early and late standardized uptake values (SUVE and SUVL, respectively); the rate constants k 1, k 2, and k 3, and the intravascular fraction v B were estimated. Changes in tumor volume were used as a response measure. Multivariate partial least-squares regression (PLSR) was used to assess if PET parameters could model tumor response and to identify PET parameters with the largest impact on response.Treatment responders had significantly larger perfusion-related parameters (k 1 and k 2) and lower metabolism-related parameter (k 3) than non-responders 10 days after the start of treatment. These findings were further supported by the PLSR analysis, which showed that k 1 and k 2 at day 10 and changes in k 3 explained most of the variability in response to therapy, whereas SUVL and particularly SUVE were of lesser importance.RESULTSTreatment responders had significantly larger perfusion-related parameters (k 1 and k 2) and lower metabolism-related parameter (k 3) than non-responders 10 days after the start of treatment. These findings were further supported by the PLSR analysis, which showed that k 1 and k 2 at day 10 and changes in k 3 explained most of the variability in response to therapy, whereas SUVL and particularly SUVE were of lesser importance.Overall, rate parameters related to both tumor perfusion and metabolism were associated with tumor response. Conventional metrics of [18F]FDG uptake such as SUVE and SUVL apparently had little relation to tumor response, thus necessitating full dynamic scanning and pharmacokinetic analysis for optimal evaluation of chemotherapy-induced changes in breast cancers.CONCLUSIONSOverall, rate parameters related to both tumor perfusion and metabolism were associated with tumor response. Conventional metrics of [18F]FDG uptake such as SUVE and SUVL apparently had little relation to tumor response, thus necessitating full dynamic scanning and pharmacokinetic analysis for optimal evaluation of chemotherapy-induced changes in breast cancers.