bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 39: Mir-21 regulates TGF-β1-induced CAF formation through Smad7
Authors: Mi Jun 
Published: August 2012

Abstract
The TGF-β1, one of major cytokines secrected by tumor cells, not only promotes the growth of tumor cells themselves, but also transforms the adjacent stroma cells into cancer-associated fibroblast formation. However, the detail mechanism by which TGF-β1 induces CAF (cancer-associated fibroblast) formation is unveiled. In this study, the primary fibroblast from skin was successfully transformed into CAF in vitro. These TGF-β1-induced CAF cells significantly promoted the tumor growth in the A175 xenografted mice model. Moreover, the TGF-β1 stimulation not only increased the amount of miR-21, but also reduced the protein level of Smad 7 in primary fibroblast. The TGF-β1 accelerated the Drosha-mediated miR-21 maturation and the Smad 7 was identified to be a target of miR-21. Both the overexpression of miR-21 and knocking down of Smad 7 induced the CAF formation, which represented the TGF- β1 triggered phenotype in primary fibroblast. The Smad 7 physically associates with the Smad 2/3 and regulates the activation of Smad 2/3. The activation of Smad signaling globally changed the status of chromatin and triggered the reprogramming process and transformed the primary fibroblast into CAF.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 39. doi:1538-7445.AM2012-39
Abstract 3902: Development of Aurora A inhibitors with ortho-halophenyl substituted pyrimidines: Unusual potency, SAR and X-ray crystallography studies.
Authors: Lawrence Harshani R. , Martin Mathew P. , Luo Yunting , Pireddu Roberta , Gevariya Harsukh , Ozcan Sevil , Zhu Jin-Yi , Rodriguez Mercedes , Elias Roy , Yang Hua , Sebti Said M. , Schonbrunn Ernst , Lawrence Nicholas J. 
Published: August 2012

Abstract
The Aurora kinases are a family of serine-threonine kinases that play an important role in the regulation of cell division. The three members of the Aurora family Aurora A, B and C share a high degree of structural homology in their kinase domain but each kinase plays a different role in the control of mitosis. Aurora A and B have received the most attention to date as anticancer targets. Detailed studies have shown Aurora A and B are over expressed in a variety of cancers and are implicated in many aspects of tumor development. Aurora A is frequently over-expressed in tumors and cancer cell lines and has characteristics of an oncogene. Aurora B is also over expressed in many cancer types but does not have oncogenic properties. Aurora B plays important roles in M phase to ensure correct chromosome-microtubule alignment and attachment and chromosomal cytokinesis. Therefore, inhibition of Aurora kinase A and B is emerging as target-based therapy in cancer treatment. From our previous work HLM-8598 was identified from an in-house chemical library as a potent and highly selective inhibitor for Aurora A (IC50 value of 0.073 ± 0.002 μM) over Aurora B (IC50 = 5.4 ± 1.8 μM). X-ray crystallography studies of HLM-8598 bound to Aurora A confirmed HLM-8598 is a type-1 kinase inhibitor that interacts with the ATP binding site of the enzyme. The HLM-8598 bound to Aurora A structure-assisted synthesis of new analogs with IC50 &lt; 2.5 nM affinity. We will present the synthesis of new analogs that contain an ortho-halogen substituted phenyl moiety, structure activity relationship studies as a part of our efforts to identify unusually potent Aurora A kinase inhibitors. We will discuss the use of kinase structural elements to rationally guide compound synthesis and improve design strategy. The in vitro and in vivo activities of ortho-halogen phenyl substituted pyrimidines will be presented as unusually potent Aurora A inhibitors and potential anti-cancer agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3902. doi:1538-7445.AM2012-3902
Abstract 3905: Synthesis and structure activity relationship of substituted N,6-diphenyl-5,6-dihydrobenzo[h]quinazolin-2-amine as inhibitors of fibroblast growth factor receptors (FGFR)
Authors: Ali Syed M. , Brassard Chris , Dalton Audra , Kizer Darin , Lapierre Jean-Marc , Liu Yanbin , Moussa Magdi , Palma Rocio , Tandon Manish , Vensel David , Volckova Erika , Wang Jianqiang , Westlund Neil , Wu Hui , Yang Rui-Yang , Bates Craig , Bhavsar Mayank , Bull Cathy , Eathiraj Sudharshan , Nicewonger Robert , Savage Ron , Waghorne Carol , Castro Jennifer , Nakuci Enkeleda , Chen Chang-Rung , France Dennis S. , Chan Thomas C.K. , Ashwell Mark A. 
Published: August 2012

Abstract
Utilization of hydrophobic motifs present in auto-inhibited protein kinases has resulted in the identification of a series of 5,6-dihydrobenzo [h]quinazolin-2-amines with activity as fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors. Herein we describe the combination of a proprietary in silico design process, a new screening paradigm using an array of biochemical and biophysical technologies in conjunction with an established parallel chemistry process for the identification and optimization of a series of novel FGFR inhibitors. These potent FGFR inhibitors exhibit a preference for the inactive form of the kinase, are non-ATP competitive, and exhibit robust cellular pharmacodynamic inhibition as well as in vitro anti-proliferative effects in cells dependent on FGFR and significant anti-tumor activity in appropriate xenograft models in vivo. The design strategy, synthesis, structure activity relationships and in vitro and in vivo biology of selected inhibitors will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3905. doi:1538-7445.AM2012-3905
Abstract 3908: Norton-Simon modeling for the optimization of dose and schedule of palifosfamide in breast cancer
Authors: Traina Tiffany A. , Hudis Clifford , Lewis Jonathan , Norton Larry 
Published: August 2012

Abstract
Palifosfamide (P), the stabilized active metabolite of ifosfamide, is a bifunctional DNA alkylating agent with broad anticancer activity, including against cells with ALDH over-expression resistant to cyclophosphamide. In contrast to other agents of its class, P's favorable safety profile, rapid onset of action, and comparable activity by IV and PO routes permits optimization of dose-schedule. To this end we used Norton-Simon Modeling to analyze the growth curves of the MX-1 breast cancer xenograft model, unperturbed and perturbed by various dose-schedules of P. This method fits an equation ΔN(t)/αt=F(N)·G(t) to experimental data on tumor size N as a function of time t to define the magnitude and shape of the curve of growth perturbation G as a function of time t before, during, and after the administration of anticancer therapy. In general (as in this case), growth perturbation “peaks” at a number of days after administration and declines thereafter. This is largely due to the induction of spontaneously reversible resistance (tachyphylaxis) as evidenced by the cancers’ reversion to drug sensitivity after a period of drug absence. Hence, repeated cycles of intermittent therapy allows for further growth perturbation, providing for sustained anticancer effect. The solution of the Norton-Massague equation ΔN(t)/αt=aN^b-cN^d fit unperturbed growth exactly (r^2=0.99973). 180 mg/kg as a single dose caused tumor volume regression with a peak growth perturbation at 7 days after administration. The effect of lower dose levels in (growth perturbation as a % of that of 180 mg/kg as a single dose; peak at days after start of administration) were 120 mg/kg (75%; 7), 80 mg/kg (34%; 5), and 53 mg/kg (16%; 3). When P was given in divided doses over 5 days, 180 mg/kg cumulative dose resulted in (94%; 10), 120 mg/kg (55%; 6), and 80 mg/kg (16%; 3). Hence, the administration of P over 5 days preserved almost full efficacy but delayed the time of emergence of drug resistance by 43% (from 7 days to 10 days). Moreover, analysis of the effects of P alone, docetaxel alone, and the simultaneous combination indicates that the shapes and magnitudes of the single-agent curves add to perfectly predict that of the combination, with minimal loss of single-agent activity. Hence, the daily x 5 schedule (9 days off) at highest tolerated dose level is proposed for clinical study, both as a single agent and in combination with other anticancer medications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3908. doi:1538-7445.AM2012-3908
Abstract 3911: Infrared vibrational frequency as a novel molecular descriptor for lead optimization of PKB/Akt inhibitors
Authors: Kawakami Joel K. , Harrison Kristin , Baldauf Ashley , May Heidi 
Published: August 2012

Abstract
We report the use of a novel molecular descriptor used for lead optimization of PKB inhibitors. Lead optimization remains a major rate limiting step in drug discovery. Current methods for lead optimization that leads to a clinical candidate often fail during clinical trials with attrition rate as high as 9 out of 10. We re-investigated the lock and key theory by incorporating the vibrational frequency of small molecules. The vibrational frequency is calculated based on the summation of all theoretical infrared vibrational frequency of each bond and normalized via division by its molecular weight. We term this molecular descriptor as MDIR. The MDIR is utilized as a rapid lead optimization computational chemistry method. The MDIR correlation to affinity/inhibition at several molecular targets shows a parabolic relationship. Quinoxalines with MDIR values near 135 provide the best inhibition (19% INH at 10 uM) at PKB/Akt as assessed via the Cisbio HTRF KinEASE assay. An internal control, 10-DEBC, known to have 100 % inhibition of PKB at 2.5 uM, had only a 6 % INH @ 10 uM in the KinEASE assay.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3911. doi:1538-7445.AM2012-3911
Abstract 3916: Inhibition of GREB1 mRNA and protein limits ER+ breast tumor cell proliferation
Authors: Hnatyszyn H. James , Olson Rebecca , Pierce Rachel , Herbert Lynn , Lippman Marc E. 
Published: August 2012

Abstract
Discovering the mechanism by which estrogen regulates breast cancer growth will aid in the identification of patients who will benefit from endocrine therapy. Estrogen (E2) binding to the estrogen receptor (ER) stimulates the proliferation of normal mammary cells and some breast cancers. Preventing ER expression or receptor-ligand interaction in hormone-responsive breast cancers inhibits cell division and promotes tumor cell death. However, the mechanism of E2-regulated breast cancer cell growth remains unclear. Although E2-regulated genes have been identified, those critically involved in growth regulation remain elusive. Identification of critical E2-regulated genes involved in mammary cell proliferation would elucidate the key pathway(s) supporting hormone-mediated tumor growth as well as provide insight into mechanisms of resistance to endocrine therapies and potential prognostic and therapeutic targets for ER+ breast cancer treatment. Gene regulated in breast cancer 1 (GREB1) is an estrogen-regulated gene that has been implicated in hormone-stimulated cell proliferation and is a candidate clinical marker for response to endocrine therapy. GREB1 mRNA and protein expression correlate with ER expression in breast tumors and the addition of estrogen to ER+ breast cancer cell lines leads to an increase in GREB1 expression and cell proliferation. The function of GREB1 and its role in ER+ breast tumors remains undefined. Experiments were designed to elucidate the role of GREB1 in ER+ breast cancer cell lines. ER+ breast cancer cell lines were transfected with GREB1-specific siRNA and control species. These tumor cell populations were evaluated for GREB1 mRNA and protein expression, cell growth and proliferation as well as invasion and migration in vitro. Sequence-specific siRNA effectively inhibited GREB1 mRNA and protein expression for more than 96 hours in MCF7 and T47D ER+ breast tumor cell lines. Utilizing the real-time Xcelligence system to monitor cell growth in culture suggested tumor cells treated with siRNA targeting GREB1 had significantly retarded cell proliferation. These observations suggest that GREB1 is a critical E2-regulated gene involved in breast tumor cell proliferation and is an exploitable target for novel breast cancer therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3916. doi:1538-7445.AM2012-3916
Abstract 392: The role of post surgical inflammation in tumor progression in breast cancer
Authors: Rincon Mercedes , James Ted , Bunn Janice 
Published: August 2012

Abstract
Introduction The process of chronic inflammation inducing malignant transformation is well known and recognized in several disease states, including ulcerative colitis (colorectal carcinoma), chronic wounds (squamous cell carcinoma), and hepatitis B infection (hepatocellular carcinoma) as common examples. Recent evidence suggests that this process may be relevant in other tumor types and may be influenced by inflammation arising secondary to interventional procedures. The purpose of this study is to investigate the potential role of inflammatory mediators resulting from the post-surgical healing process on tumor proliferation and progression to metastasis in breast cancer. Methods We used MMTV-PyV MT female mice (transgenic mice expressing the middle T antigen of the polyomavirus under the control of the MMTV promoter/enhancer) as a mouse model of human epidermal breast cancer. Mice underwent a surgical punch biopsy (2 mm) in the center of the tumor, or underwent the same procedure (transient anesthesia) without biopsy. Mice were paired according to the tumor size at the time of biopsy. Mice were then euthanized 8 days after biopsy, and lungs were harvested and histologically examined for the presence of micrometastases. To further evaluate the effect of inflammation in the development of metastases, a separate subset of mice were treated with ibuprofen versus vehicle (placebo control) for three days after biopsy. Results No substantial difference in the primary tumor growth was observed after biopsy between the various groups. However, a greater number of metastases were found in the lungs of mice that underwent biopsy relative to the number in mice that did not receive biopsy. The number of metastases was reduced in the set of mice receiving ibuprofen treatment following the biopsy procedure (9.3 vs. 25 p&lt;0.05). Conclusion Our study provides evidence to suggest that inflammatory mediators arising secondary to the healing process may stimulate tumor proliferation and metastasis. These findings may hold significance for the timing of breast cancer treatment following diagnostic needle biopsy, as well as for the potential impact of excisional biopsy on the outcome of patients with breast cancer. Further research into the mechanisms of this interaction may help to increase our understanding of breast cancer biology and may yield new strategies (e.g. anti-inflammatory medication) to optimize treatment and outcome.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 392. doi:1538-7445.AM2012-392
Abstract 3920: Off-target effects of the putative G-protein coupled estrogen receptor 1 (GPER) agonist G1 in ovarian and breast cancer cells
Authors: Wang Cheng , Jiang Chao , Lv Xiangmin , Fu Lan , Davis John S. 
Published: August 2012

Abstract
G-protein coupled estrogen receptor 1 (GPER or GPR30) plays important roles in mediating estrogen action in many different tissues and organs under both physiological and pathological conditions. G-1 (1-[4-(6-bromobenzo[1,3]dioxol-5yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone), the putative selective GPER agonist, has been reported to activate GPER, trigger several signaling pathways, and stimulate cell proliferation in ER-negative breast cancer, endometrial and ovarian cancer. More recently, reports showed that activation of GPER by estrogen or G1 can suppress certain cell proliferation. This study was initiated to clarify the function of GPER and its agonist on the granulosa cell tumor (GCT) cell proliferation using KGN cell as a cellular model. Well characterized epithelial ovarian cancer and breast cancer cell lines were used for comparison. GPER siRNA was used to knock down GPER. Western blot and immunohistochemistry were used to detect protein expression. We found that knockdown of GPER significantly (P &lt; 0.05) suppressed KGN cell proliferation, suggesting that GPER may play positive roles on KGN cell proliferation. Low concentrations of G1 (&lt;500nM) had no effect on KGN cell proliferation, whereas higher concentrations (&gt;1μM) of G1 significantly suppressed KGN cell proliferation and arrested KGN cells in G2/M phase. These results indicated that G1 may suppress KGN cell proliferation in a GPER-independent manner. Supporting our hypothesis, knockdown of GPER did not block the inhibitory effect of G1on KGN cell proliferation. Moreover, G15, a potent GPER antagonist, failed to block G1-induced suppression of cell proliferation and G1-induced cell cycle arrest in KGN cells. In IGROV-1 epithelial ovarian cancer cells, G1 suppressed cell proliferation, a response which was not blocked by G15, even at concentrations 8-fold higher than that of G1. G1 treatment also suppressed the proliferation of MDA-MB-231 breast cancer cells, a cell line which reportedly expresses very low amounts of GPER. In HEK-293 cells, which are reported to have no expression of GPER, G1 also significantly suppressed the cell proliferation and induced cell cycle arrest. In conclusion, our results demonstrate that G1 is able to suppress ovarian and breast cancer cell proliferation in a GPER-independent manner. G1 may be a candidate for the development of drugs against ovarian and breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3920. doi:1538-7445.AM2012-3920
Abstract 3923: Growth hormone activates ERK via EGFR, not IGF-IR, to potentiate estrogen-dependent breast cancer cell proliferation
Authors: Felice Dana L. , Unterman Terry G. , Swanson Steven M. , Frasor Jonna 
Published: August 2012

Abstract
Estrogen receptor (ER) and insulin-like growth factor-I receptor (IGF-IR) interact and activate one another in breast cancer cells, and ER can up-regulate components of the IGF-I signaling pathway. Therapeutic strategies co-targeting ER and IGF-IR in ER-positive breast tumors have been developed, yet clinical trials of anti-IGF-IR therapies have not been as successful as had been hoped. Although growth hormone (GH) is implicated in having a role in breast cancer, its effects are often attributed to the actions of IGF-I. Since inhibition of IGF-IR can cause an increase in circulating levels of GH, we considered the possibility that GH may act directly on the tumor itself thus explaining the limited efficacy of anti-IGF-IR therapy in breast cancer. Therefore, we sought to determine whether GH has direct, IGF-I-independent effects on breast cancer. We demonstrate in T47D human breast cancer cells that while GH alone only weakly stimulates cell proliferation, it significantly enhances estradiol (E2)-stimulated proliferation. Inhibition of IGF-IR reduced E2-stimulated proliferation, confirming previous findings. Remarkably, GH+E2 overcame the IGF-IR blockade to promote proliferation. This indicates that GH not only acts in an IGF-I-independent manner, but can bypass IGF-IR inhibitors to restore E2 action on proliferation. Furthermore, we found that both epidermal growth factor receptor (EGFR) and ERK were required for proliferation stimulated by GH and E2, and that GH uses EGFR to activate ERK even in the presence of the IGF-IR inhibitor. Expression of proliferation genes up-regulated by GH+E2 treatment was abrogated by the EGFR and MEK inhibitors, but not by the IGF-IR inhibitor. Thus, we propose that while E2-stimulated proliferation requires IGF-IR, EGFR, and ERK, the presence of GH allows E2 to bypass the requirement for IGF-IR while remaining dependent on EGFR and ERK. Furthermore, we have found that GH can potentiate E2 stimulation of ER target gene transcription and this is dependent on ERK, but not on IGF-IR. Taken together, these findings indicate that GH not only can act directly on breast cancer cells independently of IGF-I, but can bypass IGF-IR blockade to stimulate ERK and potentiate E2 activity on proliferation and gene regulation. A better understanding of the interactions between GH and E2 will contribute to the development of novel drugs or improved combination therapies targeting the GH/IGF/E2 axis in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3923. doi:1538-7445.AM2012-3923