bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 718: The effects of trastuzumab, paclitaxel, and carboplatin on HER2-positive cancer stem cells that are isolated from primary breast cancer cultures: a preliminary report
Authors: Artac Mehmet , Kayadibi Gozde , Ceylan Ayca , Kars Meltem Demirel , Artac Hasibe , Cakır Murat , Boruban Cem , Tekin Ahmet , Tavlı Lema , Kartal Adil 
Published: August 2015

Abstract
Introduction:
It is generally accepted that trastuzumab has only effective in HER2+ breast cancer patients who have HER2 gene amplification or HER2 over expression. On the other hand, trastuzumab resistance is a problem in HER2+ patients. Our aim is to investigate the effects of trastuzumab, paclitaxel and carboplatin on cancer stem cells which is isolated from primary breast cancer cultures.
Methods:
Tumor tissue was obtained in the routine surgery of a breast cancer patient who was HER2+ by immunohistochemistry. Primary breast cancer culture were established. CD44+CD24- and ALDH+ breast cancer stem cells were sorted by flowcytometry from these culture. HER2 receptor status of the sorted cells was also determined by flowcytometry. HER2+ and HER2- breast cancer stem cells were treated with trastuzumab, paclitaxel and carboplatin, and combination of these drugs by checker board microplate method for 96 h. For all of these breast cancer stem cell subgroups, the responses to the drugs were determined.
Results:
Breast cancer stem cells were isolated from a HER2+ breast cancer patient. The cell sorting analysis results demonstrates that 43% of the population is CD44+CD24- and 22% of the population is ALDH+. CD44+CD24- breast cancer stem cell subpopulation contains 84% HER2+ and 16% HER2- cells. Carboplatin has the highest antiproliferative effect on cancer stem cells among the three drugs which means carboplatin application resulted in the lowest IC50 values in all subgroups (IC50: 0.26 μM- 0.41 μM). HER2- cancer stem cells are more resistant to the drugs (1.5- 2 fold resistance) than HER2+ subcultures. Although combination of drugs exerted synergistic effect on the subcultures, ‘breast cancer stem cells’ were found to be more resistant to the combination therapy by exhibiting higher proliferation in drug combinations.
Conclusions:
HER2- cancer stem cells may be one of reason for trastuzumab resistance in HER2+ breast cancer patients. The result of this experimental study may be used to suggest new treatment strategies in HER2+ breast cancer patients.
Citation Format: Mehmet Artac, Gozde Kayadibi, Ayca Ceylan, Meltem Demirel Kars, Hasibe Artac, Murat Cakır, Cem Boruban, Ahmet Tekin, Lema Tavlı, Adil Kartal. The effects of trastuzumab, paclitaxel, and carboplatin on HER2-positive cancer stem cells that are isolated from primary breast cancer cultures: a preliminary report. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 718. doi:10.1158/1538-7445.AM2015-718
Abstract 722: Caveolin-1-dependent endocytosis enhanced chemosensitivity of TDM-1 in HER-2-positive breast cancer cells
Authors: Chung Yuan-Chiang , Wei Wan-Chen , Chang King-Jen , Chao Wei-Ting 
Published: August 2015

Abstract
Trastuzumab emtansine (TDM-1, kadcyla) is the antibody drug conjugate (ADC) was approved to treat HER-2 positive metastatic breast cancer. Although its effectiveness, however, the biomarker of drug resistance of TDM-1 has not been identified. The efficacy of ADC is restricted to the antibody internalization in the cell; therefore, the drug sensitivity may be associated with cellular vesicle trafficking system. Caveolin-1, which is the 21 KD membrane protein that is required for caveolae structure formation and membrane endocytic transport. In this study, the relationship of caveolin-1 expression and the chemosensitivity of TDM-1 in HER-2 positive breast cancer cells was investigated. Immunohistochemical staining of 32 specimens of breast cancer patients were evaluated for caveolin-1 expression. For in vitro study, BT-474 and SKBR-3 breast cancer cells which represent different caveolin-1 expression were treated with trastuzumab or T-DM1. Cell viability and molecular localization were examined. Cellular caveolin-1 expression was also manipulated by transfection of GFP tagged caveolin-1 or caveolin-1 shRNA plasmid, cell viability was then determined after drug treatment. In the results, Immunohistochemical study showed 68% (22/32) overexpression of Caveolin-1 in breast cancerous specimens. And eight cases with high expression of Caveolin-1 were found in HER-2 positive breast cancerous patients (72.1%, 8/11). In cell biology study, T-DM1 was found colocalized with caveolin-1 by confocal microscopy. SKBR-3 which represents higher caveolin-1 expression than BT-474 was more sensitive to T-DM1 treatment. After molecular transfection, BT-474 cells with overexpression of caveolin-1 increased chemosensitivity in the treatment of TDM-1, instead, SKBR-3 cells transfected with caveolin-1 shRNA decreased T-DM1 sensitivity. Expression of caveolin-1 could mediate endocytosis and promoting the internalization of TDM-1 into HER-2 positive cancer cells. Thereafter, caveolin-1 may be an effective predictor for TDM-1 treatment in the future.
Citation Format: Yuan-Chiang Chung, Wan-Chen Wei, King-Jen Chang, Wei-Ting Chao. Caveolin-1-dependent endocytosis enhanced chemosensitivity of TDM-1 in HER-2-positive breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 722. doi:10.1158/1538-7445.AM2015-722
Abstract 723: GRB7 promotes doxorubicin resistance in triple-negative breast cancer cells via multiple signaling pathways
Authors: Lofgren Kristopher A. , Calvo Verónica , Giricz Orsi , Kenny Paraic A. 
Published: August 2015

Abstract
Triple-negative breast cancer (TNBC) lacks expression of the estrogen and progesterone steroid receptors and HER2; thus TNBC patients cannot benefit from the recent successes of targeted therapies, and instead rely on cytotoxic chemotherapeutic cocktails. As such, tumor recurrence is high and patient prognosis is poor.
GRB7 is a soluble adaptor protein required for cell migration, invasion, and proliferation in TNBC. We have previously reported that a high GRB7 mRNA level was the strongest predictor of tumor recurrence in a cohort of 246 TNBC patients treated with doxorubicin. GRB7 was confirmed in a smaller, independent cohort as an indicator of poor prognosis. After the observation of both decreased doxorubicin sensitivity and elevated GRB7 expression levels in TNBC tumors, we hypothesized that GRB7 was mediating a signaling pathway critical for drug resistance and cell survival.
The current study utilizes isogenic MDA-MB-231 breast cancer cell lines to examine the impact of altered GRB7 levels on TNBC cell signaling and chemosensitivity. Through stable overexpression and knock-down of GRB7, we have identified multiple downstream kinases with altered phosphorylation in basal growth conditions (Akt, Erk, and Jnk) that remain responsive to EGF stimulation. Treatment of TNBC cell lines with G7-18NATE, a specific peptide inhibitor of GRB7, sensitized TNBC cells to doxorubicin. Therefore, we created stable cell lines with constitutively active Akt and Map2k1 and the overexpression of MKK7 in order to determine whether the activation of these kinases individually have novel roles in GRB7-mediated chemoresistance and TNBC cell biology associated with the malignant phenotype, such as cell migration and invasion.
This study provides a strong rationale for targeting GRB7 or GRB7-dependent pathways in combination with cytotoxic chemotherapy for GRB7-high TNBC patients. Delineating the signaling events downstream of GRB7 in TNBC could provide further insight into improving the therapeutic index with combinatorial approaches.
Citation Format: Kristopher A. Lofgren, Verónica Calvo, Orsi Giricz, Paraic A. Kenny. GRB7 promotes doxorubicin resistance in triple-negative breast cancer cells via multiple signaling pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 723. doi:10.1158/1538-7445.AM2015-723
Abstract 725: Restoration of miR-100 sensitizes luminal A breast cancer to paclitaxel treatment by targeting mTOR
Authors: Zhang Baotong , Zhao Ranran , He Yuan , Fu Xing , Dong Jin-Tang 
Published: August 2015

Abstract
Based on molecular profiling, immunohistochemical detection of ERα, PR and Her2, and morphological evaluation, breast cancer is classified into five subtypes: Luminal A, Luminal B, Her2, Basal-like, and Normal-like. Each subtype has distinct prognosis and treatment response. The luminal A subtype nicely responds to endocrine therapy with a good prognosis, but is less responsive to chemotherapies including paclitaxel. According to a previous study, patients with luminal A breast cancer do not benefit from the addition of paclitaxel to their chemotherapies, but the underlying mechanisms are still not clear. We found that the expression of miRNA miR-100 is dramatically lower in luminal breast cancer cell lines compared to the basal-like subtype. In human breast cancer specimens, while miR-100 expression was downregulated when compared to the matched normal breast tissues, the downregulation in luminal A subtype tumors was more dramatic when compared to other subtypes. We therefore propose that lower levels of miR-100 expression could be responsible for decreased sensitivity of luminal A breast cancer to paclitaxel. To test this hypothesis, we expressed miR-100 in the MCF-7 luminal A breast cancer cell line, and found that expression of miR-100 sensitized MCF-7 cells to paclitaxel treatment by promoting paclitaxel-induced apoptosis and cell cycle arrest. We also suppressed miR-100 expression in the MDA-MB-231 basal-like cell line, and found that miR-100 downregulation desensitized MDA-MB-231 cells to paclitaxel. Tumorigenesis experiments in nude mice further support a role of miR-100 in luminal breast cancer's response to paclitaxel treatment. mTOR, an important player in the PI3K/mTOR signaling pathway, has been identified as a downstream target of miR-100, and combination of rapamycin, a mTOR inhibitor, with paclitaxel enhances the effect of chemotherapy in breast cancer. We found that miR-100 expression inhibited mTOR expression in MCF-7 cells, while suppression of miR-100 increased mTOR expression in MDA-MB-231 cells. These results suggest that miR-100 sensitizes luminal A breast cancer cells to paclitaxel via targeting mTOR. They also provide an explanation for the resistance of luminal A breast cancer to paclitaxel treatment.
Citation Format: Baotong Zhang, Ranran Zhao, Yuan He, Xing Fu, Jin-Tang Dong. Restoration of miR-100 sensitizes luminal A breast cancer to paclitaxel treatment by targeting mTOR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 725. doi:10.1158/1538-7445.AM2015-725
Abstract 726: Constitutive NF-kB-activation loop enhances resistance to trastuzumab in HER2 positive luminal B breast cancer
Authors: Kanzaki Hirotaka , Makhopadhya Nishit , Cui Xiaojiang , Ramanujan Krishnan V. , Takeda Tatsuaki , Kitamura Yoshihisa , Sendo Toshiaki , Murali Ramachandran 
Published: August 2015

Abstract
[Purpose]
Luminal B breast cancer patients are significantly at the risk of relapse with in 5 years. Acquired resistance to the receptor tyrosine kinase HER2 targeting antibody trastuzumab is a major clinical problem in the treatment of recurrent HER2-positive breast cancer. The molecular mechanisms leading to trastuzumab resistance (TZR) remain unclear in luminal B breast cancer. Here, we investigated the mechanism of TZR in HER2-positive luminal B breast cancer cells with acquired resistance.
[Methods and Results]
We generated trastuzumab resistant breast cancer cell line (BT-474-R) by treating BT-474 cells with trastuzumab for over long-term. Initial validation showed that HER2 overexpression in the BT-474-R cells remained unaltered suggesting that probably HER2 independent signaling pathway is involved in the development of TZR. We demonstrated that NF-κB is constitutively activated in the BT-474-R cells by quantitative realtime RT-PCR, western blotting and immunofluorescent microscopy. Expression of pro-inflammatory cytokines were also demonstrated. Pharmacologic inhibition of NF-κB improved sensitivity to trastuzumab in BT-474-R cells. We identified both IKK-α and IKK-β as the major determinants of the activation of the NF-κB signaling in the resistant cells.
[Conclusion]
Our study suggests by activating NF-κB pathway, luminal B cells may facilitate acquiring basal-like, Her2+ phenotype a notion consistent with “progression through grade” hypothesis. Finally, our study suggests that blocking NF-κB will provide a new treatment option to limit relapse in HER2 positive breast cancer patients treated with trastuzumab.
Citation Format: Hirotaka Kanzaki, Nishit Makhopadhya, Xiaojiang Cui, Krishnan V. Ramanujan, Tatsuaki Takeda, Yoshihisa Kitamura, Toshiaki Sendo, Ramachandran Murali. Constitutive NF-kB-activation loop enhances resistance to trastuzumab in HER2 positive luminal B breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 726. doi:10.1158/1538-7445.AM2015-726
Abstract 730: The role of ZEB1/ZEB2 and βIII-tubulin in mediating docetaxel-resistant prostate cancer
Authors: Hanrahan Karen , Prencipe Maria , Bugler Jane , Murphy Lisa , O'Neill Amanda , Watson R. William 
Published: August 2015

Abstract
Docetaxel therapy is the gold standard treatment for advanced castrate-resistant prostate cancer (CRPC). However, patients either do not respond or develop resistance over time. Transcriptomic and proteomic analysis of docetaxel-resistant prostate cancer sub-lines developed by our group revealed multiple mechanisms of resistance in line with advanced disease, including over-expression of anti-apoptotic proteins and alterations of NF-KB activation. The sub-lines also demonstrated a coordinated loss and gain of epithelial and mesenchymal markers respectively; a process characteristic of Epithelial-Mesenchymal Transition (EMT). Studies have highlighted a role of EMT in prostate cancer progression, metastasis and docetaxel resistance. However, the role of EMT drivers in mediating resistance is not defined. We hypothesise EMT to be a central mechanism of apoptotic resistance in advanced docetaxel-resistant prostate cancer, representing a target for therapeutic manipulation.
EMT was characterised in the PC-3 D12 and DU145 R docetaxel-resistant sub-lines through an increased invasive capacity, MMP-1 secretion and protein expression of E-cadherin transcriptional repressors ZEB1 and ZEB2, in comparison to parental cell lines. This was associated with an increased expression of βIII-tubulin; a tubulin isotype linked to taxane resistance and tumour aggressiveness. Upon treatment with the apoptotic trigger docetaxel (20nM), the PC-3 D12 and DU145 R sub-lines demonstrated significant resistance compared to parental controls. Simultaneous siRNA knockdown of ZEB1 and ZEB2 resulted in both a partial reversal in apoptotic resistance and a decrease in cell viability; this was also associated with a down-regulation of βIII-tubulin and a re-expression of E-cadherin.
Our results provide evidence of the process of EMT in in vitro models of docetaxel-resistant prostate cancer, which is associated with differential susceptibility to docetaxel and is partially reversed through siRNA knockdown of the EMT drivers, ZEB1 and ZEB2. In addition, we have identified a link between EMT and βIII-tubulin in our models of docetaxel resistance. Current experiments are investigating the tissue expression of ZEB1 and βIII-tubulin in prostate cancer metastases following docetaxel therapy, which will determine the clinical relevance of EMT and βIII-tubulin as mediators of docetaxel resistance in CRPC.
Citation Format: Karen Hanrahan, Maria Prencipe, Jane Bugler, Lisa Murphy, Amanda O'Neill, R. William Watson. The role of ZEB1/ZEB2 and βIII-tubulin in mediating docetaxel-resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 730. doi:10.1158/1538-7445.AM2015-730
Abstract 733: A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer
Authors: Vidal Samuel J. , Rodriguez-Bravo Veronica , Quinn Aidan , Williams Estrelania , de la Iglesia-Vicente Janis , Sun Xiaochen , Chen Xintong , Hoshida Yujin , Cordon-Cardo Carlos , Domingo-Domenech Josep 
Published: August 2015

Abstract
Castration resistant prostate cancer (CRPC) is a significant cause of mortality worldwide. In recent years, treatment modalities that improve survival have emerged including taxane chemotherapy and second generation androgen signaling inhibitors, among others. Indeed, today the first line chemotherapeutic docetaxel as well as the second line agent cabazitaxel are mainstays of treatment. However, CRPC inexorably progresses to a chemotherapy resistant state that ultimately precedes lethality. Elucidating the molecular determinants of aggressiveness in chemotherapy resistant CRPC may therefore stimulate new therapeutic strategies that improve clinical outcomes. We used laboratory models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Whole genome expression profiling, clinical validation and genetic screening approaches revealed that GATA2 regulates a consensus signature of cancer progression associated genes. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a significant mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this axis prompted a novel combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in chemotherapy resistant prostate cancer and identify a therapeutic opportunity in this challenging disease.
Citation Format: Samuel J. Vidal, Veronica Rodriguez-Bravo, Aidan Quinn, Estrelania Williams, Janis de la Iglesia-Vicente, Xiaochen Sun, Xintong Chen, Yujin Hoshida, Carlos Cordon-Cardo, Josep Domingo-Domenech. A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 733. doi:10.1158/1538-7445.AM2015-733
Abstract 734: Synergistic antitumor effect of vemurafenib and metformin in thyroid cancer
Authors: Hanly Elyse K. , Tuli Neha Y. , Bednarczyk Robert B. , Moscatello Augustine L. , Darzynkiewicz Zbigniew , Geliebter Jan , Tiwari Raj K. 
Published: August 2015

Abstract
Advanced thyroid cancer patients such as those with radioiodine-refractory and metastatic differentiated thyroid cancer or anaplastic thyroid cancer lack effective treatment options. Targeted BRAF kinase inhibitors such as vemurafenib have shown promising results in clinical trials and off-label use for patients with BRAFV600E-positive tumors. While targeting BRAFV600E offers particular effectiveness and selectivity in inhibiting cancer cells in the short term, resistance does develop. Prior results in our laboratory confirmed that vemurafenib halts DNA synthesis and induces apoptosis in our mutated thyroid cancer cells. In addition, resistant BCPAP (papillary thyroid cancer) cells were developed in our laboratory by exposing cells to increasing concentrations of vemurafenib. Resistant cells were characterized by hyperactive mitogen-activated protein kinase (MAPK) signaling and resistance to mammalian target of rapamycin (mTOR) inhibition. These additional targets mediating resistance provide an opportunity to devise novel synergistic combination therapies. Since antitumor effects of the widely used antidiabetic agent metformin were observed in thyroid cancer cells and the drug is thought to suppress mTOR, we investigated metformin adjuvant therapy in combination with vemurafenib. Various cell lines including Nthy-ori 3-1 (normal immortalized thyroid cells), BCPAP (papillary thyroid cancer), vemurafenib-resistant BCPAP, and 8505c (anaplastic thyroid cancer) were analyzed in terms of cellular viability, apoptosis and expression of cell signaling molecules after exposure to both drugs. We found that the combination of vemurafenib and metformin caused significantly decreased viability in vemurafenib-resistant BCPAP cells. Furthermore, synergistic apoptosis was observed in BCPAP papillary thyroid cancer cells and 8505c anaplastic thyroid cancer cells in response to the combination treatment. These effects appeared to be mediated by inhibition of both mTOR and MAPK signaling. Results support further investigation into the use of metformin in combination with targeted kinase inhibitors to treat advanced thyroid cancer patients.
Citation Format: Elyse K. Hanly, Neha Y. Tuli, Robert B. Bednarczyk, Augustine L. Moscatello, Zbigniew Darzynkiewicz, Jan Geliebter, Raj K. Tiwari. Synergistic antitumor effect of vemurafenib and metformin in thyroid cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 734. doi:10.1158/1538-7445.AM2015-734
Abstract 738: Combined inhibition of non-canonical HER2 signaling as a strategy to overcome resistance to HER2-targeted therapies
Authors: Bernardi Ronald J. , Dominguez-Vidana Rocio , Bland Christopher S. , Scorsone Kathleen A. , Tyagi Siddhartha , Schmitt Earlene M. , Shea Martin J. , Mitchell Tamika , Rao Mitchell , Nanda Sarmistha , Hilsenbeck Susan G. , Shaw Chad , Osborne C. Kent , Schiff Rachel , Westbrook Thomas F. 
Published: August 2015

Abstract
Despite the availability of drugs directly targeting HER2, resistance to therapy remains a major clinical problem in HER2-positive breast cancer. Leveraging a series of RNAi genetic screens, we identify a novel signaling network governing response to HER2 inhibition in vitro and in vivo. We define WEE1 as a core component of this network. Genetic or pharmacologic inhibition of WEE1 or its upstream regulators kills HER2-positive breast cancer cells in combination with HER-family inhibitors. Mechanistically, we demonstrate a non-canonical role of HER2 in governing mitotic progression. Combined inhibition of WEE1 and HER2 abolishes this critical regulation, leading to mitotic catastrophe and apoptosis. Thus, we demonstrate an unexpected convergence of non-canonical HER2 signaling and WEE1 that can be exploited to overcome drug resistance. Our findings provide a strong mechanistic and pre-clinical rationale for combined HER2 and WEE1 inhibition as a treatment strategy for HER2-positive breast cancer.
Citation Format: Ronald J. Bernardi, Rocio Dominguez-Vidana, Christopher S. Bland, Kathleen A. Scorsone, Siddhartha Tyagi, Earlene M. Schmitt, Martin J. Shea, Tamika Mitchell, Mitchell Rao, Sarmistha Nanda, Susan G. Hilsenbeck, Chad Shaw, C. Kent Osborne, Rachel Schiff, Thomas F. Westbrook. Combined inhibition of non-canonical HER2 signaling as a strategy to overcome resistance to HER2-targeted therapies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 738. doi:10.1158/1538-7445.AM2015-738