bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-08-05: Functional characterization of three novel breast cancer-related somatic mutations in metalloproteinase-disintegrin ADAM12
Authors: Qi Y , Duhachek-Muggy S , Li H , Zolkiewska A 
Published: August 2014

Abstract
Six different somatic missense mutations in the human ADAM12 gene have been identified so far in breast cancer. Five of these mutations involve highly conserved residues in the extracellular domain of the transmembrane ADAM12-L protein. Two of these extracellular mutations, D301H and G479E, have been previously characterized in the context of mouse ADAM12. Three other mutations, T596A, R612Q, and G668A, have been reported more recently, and their effects on ADAM12-L protein structure/function are not known. Here, we show that ADAM12-L bearing the G668A mutation is largely retained in the endoplasmic reticulum in its nascent, full-length form, with an intact N-terminal pro-domain. The T596A and R612Q mutants are efficiently trafficked to the cell surface and proteolytically processed to remove their pro-domains. However, the T596A mutant shows decreased catalytic activity at the cell surface, while the R612Q mutant is fully active and comparable to the wild-type ADAM12-L. The D301H and G479E mutants, consistent with the effect of the corresponding D229H and G477E mutations in mouse ADAM12 protein described earlier, are not proteolytically processed and do not exhibit catalytic activity at the cell surface. Among all six breast cancer-associated mutations in ADAM12-L, mutations that preserve the activity - R612Q and L792F - occur in triple-negative breast cancers, while loss-of-function mutations - D301H, G479E, T596A, and G668A - are found in non-triple negative cancers. This apparent association between the catalytic activity of the mutants and the type of breast cancer supports a previously postulated role of ADAM12-L in the triple negative breast cancer disease.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-08-05.
Abstract P2-09-07: Inhibition of aurora-A by MLN8237 decreases SMAD5 expression and increases effectiveness of chemotherapeutic agents in breast cancer cells
Authors: Opyrchal M , Iankov I , Ingle JN , Galanis E , D'Assoro AB 
Published: August 2014

Abstract
BACKGROUND: Breast cancer affects thousands of women each year. Epithelial to Mesenchymal transition (EMT) has been associated with increased metastatic potential of cancer cells as well as resistance to chemotherapy. Predicatively, presence of EMT leads to worse prognosis in patients with breast cancer. We have recently showed that Aurora-A plays a key role in development of EMT and increased ability of breast cancer cells for self renewal. Therefore we hypothesized that inhibition of Aurora-A in breast cancer cells will lead to increased sensitivity to chemotherapy.
RESULTS: Increased Aurora-A expression, as assessed by IHC staining, in patients with locally advanced disease was associated with worse prognosis. We show that in ER+ cell line, MCF7, activating MAPK pathway through overexpression of Raf1 leads to increase in Aurora-A activity. These cells have decreased sensitivity to treatment with paclitaxel when compared to untransfected cells in MTT assays. This effect is even more exacerbated with over-expression of Aurora-A. The sensitivity to paclitaxel was restored with inhibition of Aurora-A by specific inhibitor, Alisertib. This was further explored in triple negative (MDA-MB-231) or Her-2/neu expressing (SUM149) cell lines. These cells express higher levels of Aurora-A. Inhibition of Aurora-A activity in combination with paclitaxel was superior when compared to either therapy alone. Similar effect was seen with use of anthracyclines. Inhibition of Aurora-A resulted in decreased SMAD5 expression as well as decreased Akt phosphorylation. Current studies are looking at a role of Aurora-A in activating SMAD5 and its role in resistance to chemotherapy. In vivo experiments evaluating combination therapies in breast cancer animal model are ongoing.
CONCLUSIONS: Inhibition of Aurora-A by a specific inhibitor, MLN8237, resulted in decreased SMAD5 expression and increased effectiveness of chemotherapeutic agents in breast cancer cells. These results contribute to better understanding of signaling pathways involved in resistance of breast cancer cells to chemotherapy. This knowledge could be very useful in developing more effective treatments for breast cancer patients in neo-adjuvant, adjuvant and metastatic settings.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-07.
Abstract P2-09-11: Identification of a novel inhibitor of triple-negative breast cancer cell growth by screening of a small molecule library
Authors: Fujita T , Mizukami T , Okawara T , Inoue K , Fujimori M 
Published: August 2014

Abstract
Background: Triple-negative breast cancers (TNBC) are defined as not having amplification of the estrogen receptor, progesterone receptor, or epidermal growth factor receptor 2. At present, recovery in patients is severely limited following diagnosis of metastatic TNBC, with less than 30% of patients surviving more than 5 years.. The most effective therapy to date is chemotherapy, which has been unsuccessful due to the lack of therapeutic targets for these aggressive cancers. To identify new molecular targets for TNBC, we have developed a novel method for drug discovery using active compounds for identification of pharmacodynamic biomarkers.
Methods: We used chemical informatics to design a small molecule library that has structural diversity. This library was used to screen for compounds that selectively inhibit the proliferation in TNBC cell lines. The differences in gene expression profiles in cell lines before and after the addition of selected compounds were analyzed and compared with control cells.
Results: We identified (E)-3-(3,4-dihydroxybenzylidene)-benzofuran-2(3H)-one (DBBF) that exhibited specific inhibition of the proliferation in a TNBC cell line, MDA-MB-468 with IC50 of 2.4 μM. Microarray analysis identified several signaling pathways, including the irinotecan pathway, which changed specifically in the TNBC cell lines by the addition of DBBF.
Conclusion: We have developed a novel research strategy that involves screening of selective inhibitors of TNBC cell line proliferation that can be used for identification of pharmacodynamic biomarkers for TNBC. The discovery of new pathways by this technique should lead to the identification of new therapeutic targets for this aggressive cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-11.
Abstract P2-09-16: Pre-clinical evaluation of novel anti-angiogenic agents as breast cancer therapeutics
Authors: McGarrigle SA , Murphy A , Kennedy BN , Reynolds A , O'Sullivan JN , Kennedy MJ , Connolly EM 
Published: August 2014

Abstract
Background
There is a need to develop novel drugs that will improve survival in breast cancer patients. Angiogenesis is essential for breast tumour progression. To date, the most promising approach to inhibit angiogenesis in breast cancer patients has been the drug bevacizumab which targets the pro-angiogenic factor Vascular Endothelial Growth Factor (VEGF). Recently, there has been controversy regarding the efficacy of bevacizumab for breast cancer treatment. In clinical trials, bevacizumab failed to establish an overall-survival benefit and was associated with serious toxicities. This resulted in the FDA revoking approval for the drug for the first line treatment of advanced breast cancer. Due to this uncertainty surrounding the efficacy of bevacizumab for the treatment of breast cancer it is clear that there is a clinical need for more effective novel anti-angiogenic drugs with better toxicity profiles for the treatment of breast cancer.
Aim
This study aimed to identify novel small-molecule anti-angiogenic agents with therapeutic potential in human breast cancer.
Methods
Compounds with physiochemical properties consistent with drug-like compounds were screened for anti-angiogenic activity by high-throughput screening involving zebrafish larvae. Human breast tumour explants were treated with the lead compound and secretion of angiogenic factors was assessed by ELISA.
Results
We have identified a novel small-molecule agent ‘SMG1’ that significantly inhibited inter-segmental blood-vessel development in zebrafish and showed no toxicity. Treatment of breast tumour explants with SMG1 significantly inhibited secretion of the potent pro-angiogenic cytokine VEGF (p = 0.01). Furthermore, SMG1 inhibited VEGF secretion more than the standard targeted breast cancer therapies tamoxifen and Herceptin® which have been reported to inhibit angiogenesis.
Conclusion
Continuing pre-clinical work will determine if SMG1 has potential as a therapeutic agent for human breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-16.
Abstract P2-09-17: Allosteric inhibitors of the proteasome: A new concept for breast cancer treatment
Authors: Osmulski PA , Gaczynska M 
Published: August 2014

Abstract
Proteasome is an essential protease of the proteasome-ubiquitin pathway, responsible for maintaining intracellular proteostasis. It is a multifunctional, multisubunit enzyme built from interchangeable modules and intricately regulated on the molecular and cellular levels. Proteasome inhibitors display proapoptotic properties, preferentially aimed at cancerous cells. Consequently, targeted therapy with bortezomib, the competitive inhibitor of the proteasome, has been very successful with refractory/relapsed multiple myeloma and with lymphomas. Unfortunately, breast cancers performed disappointingly in clinical trials with bortezomib. We propose that a new generation of small-molecule proteasome inhibitors distinct from bortezomib may prove successful with breast cancers. In contrast to bortezomib which directly blocks proteasome active sites, the new inhibitors are allosteric ligands binding to noncatalytic sites and disrupting the enzyme's function by targeting long-distance transfer of structural signals within the enzyme's molecule. The advantages of allosteric ligands, now rapidly gaining popularity in targeted drug design, include versatility of molecular actions, defying drug resistance mechanisms, and usually high specificity with low toxicity. For example, one of the small-molecule allosteric ligands we created compromises interactions between the catalytic core proteasome and its regulatory sub-assembly 19S (“cap”, regulatory particle) responsible for recognizing and processing the majority of intracellular protein substrates tagged for degradation by polyubiquitin. We found that treatment with nanomolar concentration of the compound induced cell death in Mcf7 human breast cancer cultured cells. Interestingly, this cell line is known for its resistance to bortezomib treatment. Even more, treatment with the allosteric ligand together with bortezomib produced a synergistic effect and sensitized the Mcf7 cells to the actions of competitive inhibitor. Remarkable, the cytotoxic effects of allosteric ligand or its combination with bortezomib were not observed with the noncancerous human breast cell line, Mcf10A. Summarizing, allosteric regulation of the proteasome by small-molecule ligands, alone or in combination with established drugs competitively inhibiting proteasome, seem to be a promising strategy to utilize proteasome as a drug target in breast cancers.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-09-17.
Abstract P2-10-03: Metastasis-associated in colon cancer 1 predicts poor outcomes in patients with breast cancer
Authors: Lee JS , Cho JS , Park MH , Yoon JH 
Published: August 2014

Abstract
Background: Metastasis-associated in colon cancer 1 (MACC1) plays a role in cancer invasion and metastasis through the upregulation of hepatocyte growth factor/mesenchymal epithelial transition-pathway, which is a known critical regulator of the mitogen-activated protein kinase (MAPK) cascades. However, the potential involvement of MACC1 in breast cancer has not been assessed.
Materials and Methods: To investigate whether MACC1 expression is a prognostic marker in breast cancer, we performed immunohistochemical staining for MACC1 expression in tissue microarrays consisting of 198 invasive breast carcinomas. To demonstrate the potential correlation between MACC1 and MAPK cascades, phospho-p44/42 MAPK (ERK1/2) expression was also analyzed.
Results: Expression of MACC1 was detected in 109 (55.1%) of 198 invasive breast carcinomas. MACC1 expression was significantly associated with several clinicopathologic parameters, including ER negativity (P &lt; 0.01), PR negativity (p &lt; 0.01), and HER-2 positivity (p &lt; 0.01). The rate of metastatic relapse was significantly higher in the MACC1-positive group (87.8%, 36/41) than in the MACC1-negative group (46.5%, 73/157) (p &lt; 0.001). MACC1 expression was significantly correlated with phospho-p44/42 MAPK expression (p &lt; 0.05). On univariate survival analysis, a significant association was observed between MACC1 expression and decreased disease-free survival (p &lt; 0.001) and overall survival (p = 0.001). On multivariate analysis, MACC1 expression was one of the statistically significant independent risk factors for disease-free survival (p = 0.001).
Conclusion: Our results suggest that MACC1 may serve as a new parameter for the prognostic prediction in patients with invasive breast carcinoma. MACC1 is likely to be involved in the regulation of MAPK cascades in invasive breast carcinoma.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-10-03.
Abstract P2-10-06: Serum protein peak 3144m/z is a potential prognostic factor for postmenopausal breast cancer patients
Authors: Gao Y , Wang X-J , Xu S-H , Yang H-J , Chen Z-H , Cao W-M 
Published: August 2014

Abstract
Background: Serum protein profiles have been investigated frequently to discover predicted or prognostic biomarkers for breast cancer. Our previous studies have shown that serum protein peak 3144m/z is significantly elevated in metastatic ovarian cancer and gastric cancer. The receiver operating characteristic (ROC) curve obtained from metastatic ovarian cancer patients for differentially expressed protein peak 3144m/z showed when the cut-off value is 1.15, the sensitivity and specificity would be 65.4% and 91.4% respectively. Therefore, we investigated whether serum protein peak 3144m/z could be used as a potential prognostic tool for postmenopausal breast cancer, taking into account clinicopathological features.
Methods: Two hundred and two postmenopausal breast cancer patients from June 2006 to December 2009 were involved in this retrospective study at Zhejiang Cancer Hospital. Menopausal status of the cases was obtained through examination of the medical records. The histopathological type, lymph node metastasis, and hormone receptor status of the cases were determined by pathologists. All patients underwent conventional postsurgical treatment (chemotherapy, radiotherapy, endocrinotherapy and target therapy) and the serum samples were collected before treatment. Serum level of protein peak 3144m/z was assessed by surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Prognostic factors (lymph node metastasis status, stage, hormone receptor status and molecular subtype) were compared across subgroups of patients depending on the protein peak 3144m/z levels. Cox proportional hazards regression was used for statistical analysis.
Results: The precentage of cases with higher 3144m/z protein peak were 32.7%(66/202) in postmenopausal breast cancer patients. The serum protein peak 3144m/z was positively related to lymph node metastasis. However, there were no significant correlations between serum protein peak 3144m/z and other clinicopathological features, such as hormone receptor status, molecular subtype, clinical stage, pregnancy times and abortion history. Importantly, it was shown that patients with higher protein peak 3144m/z had significantly poorer overall survival compared with patients with lower serum protein peak 3144m/z (P = 0.0053). Furthermore, Cox multivariate regression analysis also revealed that protein peak 3144m/z was an independent prognostic factor in postmenopausal breast cancer patients (P = 0.008).
Conclusions: The protein peak 3144m/z was a poor prognostic factor in postmenopausal breast cancer patients. Further prospective and longitudinal studies are needed to evaluate whether serum protein peak 3144m/z could be used as a prognostic tool in postmenopausal breast cancer patients monitoring and management.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-10-06.
Abstract P2-11-08: IHC 2+ FISH (-) breast cancer (BC): Patient characteristics and outcomes: A comparison to HER2 IHC 0, 1+ and HER2 + BC diagnosed 2000-2006
Authors: Fehrenbacher L , Capra A , Fulton R , Habel L 
Published: August 2014

Abstract
Background: HER2 IHC 2+ results are equivocal and lead to FISH testing. FISH(+) results lead to HER2(+) treatment often with trastuzumab. FISH(-) results lead to treatment without trastuzumab. We examined the characteristics and breast cancer-specific mortality of HER2 2+ FISH (-) BC in consecutive patients in a large health care delivery system. Methods: Using the KPNC cancer registry and electronic medical record, we identified 13,845 consecutive stage I-III BC patients diagnosed between 1/2000 and 12/2006 not treated with adjuvant trastuzumab. Patient demographics, disease stage, IHC and FISH results, and breast cancer mortality were obtained. IHC and FISH testing were performed in a single central laboratory. Results: After excluding any adjuvant trastuzumab, 10,760 (78%) patients had HER2 IHC scores of 0,1+, 1,533 (11%) were IHC2+/FISH (-), and 1,552 (11%) were IHC3+ or FISH (+). Compared to patients with IHC 0,1+ tumors, those with IHC2+FISH (-) tumors were younger (mean age 61 vs 62 years, p = 0.03) and more often node+ (36% vs 30%, p = &lt;0.0001); their tumors were more often poorly differentiated (29% vs 22%, p = &lt;0.0001),) and T2 vs T1 (31% vs 24%, p = &lt;0.0001), and less frequently T1ab (20% vs 29%, p = &lt;0.0001), ER+ (81% vs 85%, p = 0.0003), or PR+ (70% vs 74%, p = &lt;0.0002). Among the ER+ patients, the 10-year BC-specific mortality was higher for those with IHC2+/FISH (-) than IHC 0, 1+ tumors (11.4% vs 8.9%, p = 0.0014). Within disease stages, there were trends but no statistical difference in BC-specific mortality. IHC3+/FISH (+) ER+ patients had greater differences in the above characteristics and significant increased mortality among middle, and higher stages. In multivariable analysis adjusting for age, tumor size, differentiation, hormonal therapy and chemotherapy, risk of BC death among ER+ patients was similar for IHC2+FISH (-) and IHC 0,1+ disease; but risk was higher for IHC3+/FISH (+) disease. Table 1: 10-year breast cancer (BC) survival of women with stage I-III ER-positive BC by HER2 subtype, 2000-2006.
10-year BC survival of stage I-III ER+ patients by IHC FISH statusHER2 SubtypeNo of PatientsBC Deathsat Risk%BC Survival95% CILogRank P-valueIHC 0,1+9,1616212,45491.190.4-91.8-IHC2+FISH(-)1,24811222388.686.3-90.60.0014IHC3+ and/or FISH(+)93512523783.680.6-86.2&lt;0.0001
Conclusions: In ER+ patients, those with IHC2+FISH (-) tumors have prognostic characteristics that are intermediate between those with IHC 0,1+ and IHC3+/FISH(+) tumors. Compared to IHC 0,1+ disease, they are at increased risk of BC mortality overall but not within stages.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-08.
Abstract P2-11-18: Immunohistochemical expression of ubiquitin ligase CHIP (carboxyl terminus of Hsc70-interacting protein) as a significant prognostic marker in postmenopausal invasive breast cancer patients
Authors: Kurozumi S , Yamaguchi Y , Matsumoto H , Takei H , Kobayashi Y , Hayashi S-I , Yanagisawa J , Horiguchi J , Takeyoshi I , Kurosumi M 
Published: August 2014

Abstract
Background:
CHIP is a U box type ubiquitin ligase that induces ubiquitination and degradation of its target proteins, which include several oncogenic proteins. We clarified that CHIP suppresses tumor growth and metastasis in human breast cancer by inhibiting oncogenic pathways (Nat Cell Biol 2009;11:312-9). In this study, we investigated the relationship between immunohistochemical CHIP expression and several biomarkers, and evaluated the correlation between CHIP expression and prognosis of patients with invasive breast cancer.
Patients and Methods:
In this study, 272 consecutive patients with invasive carcinoma of no special type with invasion &gt;5 mm, treated in 2000-2001, were enrolled. We performed immunohistochemical staining with antibodies against CHIP, ER, PgR, and HER2. Cytoplasmic expression patterns of CHIP were scored as 0 (no stain), 1 (weak stain), 2 (moderate stain), and 3 (strong stain), and divided into high CHIP (score 3) and low CHIP (score 2, 1, 0) groups. We investigated the relationship between CHIP expression and ER, PgR, HER2, histological grade (HG) and lymph node status (pN). We also evaluated correlation between CHIP expression and prognosis (RFS) of patients.
Results:
CHIP expression was as follows: score 0, 49 patients (18.0%); score 1, 91 (33.5%); score 2, 83 (30.5%); score 3, 49 (18.0%). High CHIP correlated significantly with positive ER (p&lt;0.001), positive PgR (P&lt;0.001), negative HER2 (p = 0.02), and low HG (p = 0.01). RFS was relatively better in the high CHIP group (49 patients) than the low CHIP group (223 patients) (p = 0.09). In addition, in postmenopausal patients, RFS was significantly better in the high CHIP group (23 patients) than the low CHIP group (133 patients) (p = 0.04); this was not so in premenopausal cases (p = 0.68). Furthermore, RFS was significantly better in CHIP score 3 and ER positive cases (42 patients) than in CHIP score 0 and ER negative cases (34 patients) (p = 0.03).
Conclusions:
CHIP expression correlated with status of hormone receptors and HER2 and might be a potent prognostic factor in invasive breast cancer patients, especially postmenopausal cases. Immunohistochemical examination of CHIP is thought to be useful for evaluating prognosis of breast cancer patients.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-18.