bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-06-01: The PI3K inhibitor GDC-0941 combines with trastuzumab for superior anti-tumor efficacy in HER2+ breast cancer models
Authors: De P , Sun Y , Carlson J , Friedman L , Dey N , Leyland-Jones B 
Published: August 2014

Abstract
Background: PI3K-AKT-mTOR pathway signaling is important for the oncogenic function of HER2. Activating alterations of this pathway are frequently observed in HER2-enriched breast cancer and generally herald a poor response and resistance to trastuzumab (T). Purpose: Targeting the PI3K-AKT-mTOR pathway is an attractive strategy in HER2+ breast cancer that is refractory to trastuzumab. The hypothesis is that the suppression of this pathway by pan-PI3K inhibitor, GDC-0941 may lead to overcome trastuzumab-resistance. Experimental Design: The antiproliferative and HER2-mediated cellular signaling (pAKT, pP70S6K, pS6RP, p4EBP1 and p-ERK) effects of GDC-0941 alone and in combination with T were evaluated in HER2 amplified T-sensitive (BT474), T-resistant (BT474HR), and HER2 amplified/PIK3CA mutated (HCC1954, UACC893) BT cell lines by MTT assay and Western blots. Clonogenic growth was tested by 3D ON-TOP assay and apoptosis markers were also tested. Athymic mice bearing BT474 and BT474HR xenograft tumors were treated with GDC-0941 and T (alone and in combination). Results: (1) GDC-0941 exhibited in vitro cell killing activity in MTT assay with IC50's ranging from 0.35 μM to 1 μm and potency was augmented by the addition of T, (2) inhibition of phosphorylation of AKT(S473, T308), P70S6K, S6RP, and 4EBP1(T37/46, T70) was observed following GDC-0941 treatment, and the combination of GDC-0941 and T more effectively blocked the PI3K-AKT-mTOR pathway, (3) GDC-0941 treatment increased apoptosis markers (CL-CASPASE3 and annexinV positivity), (4) GDC-0941 dose-dependently blocked 3D-ON-TOP clonogenic growth of HER2+ cells. This effect was potentiated in the presence of T and (5) in vivo, the combination of GDC-0941 and T significantly reduced established tumor growth in both sensitive (82%) and resistant (79%) models with concomitant decrease of different PD markers. Conclusions: Our data suggest that 1) therapeutic targeting of the PI3K-AKT-mTOR signaling should be effective in abrogating resistance to T therapy in HER2+ BT, and 2) targeting both the HER2 and the PI3K signaling pathways is an attractive strategy to enhance the clinical efficacy of T therapy, as well as to prevent or delay the development of resistance.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-06-01.
Abstract P5-07-02: Mutant GATA3 causes precocious lobuloalveolar development in the mouse mammary gland and is associated with more aggressive human breast cancer
Authors: Kenny PA , Chandiramani N , Peterson EA 
Published: August 2014

Abstract
GATA3 is an essential mediator of mammary gland development and is expressed at high levels in Estrogen Receptor positive tumors. This gene has recently emerged as one of the most frequently mutated genes in Estrogen Receptor positive breast cancer. GATA3 mutant tumors tend to retain and express the wild-type GATA3 allele which, together with the established role for GATA3 in maintaining luminal epithelial differentiation, has led to the suggestion that GATA3 is a haploinsufficient tumor suppressor gene in the mammary gland.
We describe a striking contrast between the GATA3 mutation spectrum in breast cancer with that found in a true GATA3 haploinsufficiency syndrome and propose that this is indicative of a strong selective pressure to mutate and retain expression of a substantial portion of the GATA3 coding sequence. We demonstrate that the proteins encoded by GATA3 mutant alleles lack the capacity to bind to canonical GATA sequence motifs and acquire a new recognition specificity governed by the N-terminal zinc finger domain. Transgenic expression of the mutant protein results in a pronounced precocious lobuloalveolar development in 9 week old female mice, suggesting that the mutant gene is not a null allele and can regulate cell proliferation. In addition, we demonstrate that Estrogen Receptor positive GATA3 mutant human breast tumors arise at earlier ages than Estrogen Receptor GATA3 wild-type tumors, which further emphasizes the clinical relevance of these mutations.
Based on the estimated mutation prevalence from the TCGA study, approximately 22,000 new cases of GATA3-mutant invasive breast cancer are diagnosed in the US each year. Collectively, our data indicate that GATA3 mutant tumors may comprise a breast cancer subset with distinct biological and clinical behavior and that a detailed understanding of the novel repertoire of target genes may yield useful clinical targets for this population.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-07-02.
Abstract P5-07-10: APOBEC3B drives mutagenesis in breast cancer
Authors: Harris RS 
Published: August 2014

Abstract
A typical breast cancer accumulates hundreds to thousands of somatic mutations. Breast cancer mutation spectra are often dominated by C-to-T transition mutations, which occur in a mostly dispersed manner but can also occur in localized clusters called kataegis. Several lines of evidence indicate that the innate immune DNA cytosine deaminase APOBEC3B is the primary cause of these mutations. First, APOBEC3B mRNA is up-regulated in the majority of primary breast tumors and breast cancer cell lines. Second, endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell line extracts. Third, APOBEC3B knockdown causes a corresponding decrease in genomic uracil concentrations, mutation frequencies, and C-to-T mutation levels in breast cancer cell lines. Fourth, the biochemical signature of APOBEC3B is over-represented in breast cancer mutation spectra. Fifth, breast carcinomas that express high levels of APOBEC3B have twice as many mutations as those expressing low levels. Finally, high levels of APOBEC3B associate with more aggressive disease including shorter durations of survival. All of these data are consistent with a model in which APOBEC3B-catalyzed DNA cytosine deamination provides a chronic source of DNA damage and mutagenesis in breast carcinomas that may help to explain how some tumors evolve rapidly and manifest gross heterogeneity.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-07-10.
Abstract P5-08-02: New target in the resistant mechanism to trastuzumab
Authors: Vu TT , Zhang Q , Tian L , Shackleford T , Kute T , Claret FX 
Published: August 2014

Abstract
Her2 positive (Her2+) breast cancer (BC) accounts for 18-20% of all breast cancer subtypes and is associated with high risk of death. Trastuzumab, the first Food and Drug Administration-approved targeted therapy for BC, represents a key milestone in the personalized treatment of Her2+ metastatic disease (Her2+ MBC). However, the median duration of response is less than a year, due to either primary or acquired resistance to the therapy. In addition, there is currently no conclusive biomarker for the response of patients to trastuzumab. Therefore, understanding the development of resistance to trastuzumab is of our interest. Recent studies have proposed various potential mechanisms leading to the resistance, including p27 rapid degradation. Previously, our study and other research demonstrated that Jab1 degrades p27 in breast cancer. These findings suggest that Jab1 over-expression contributes to trastuzumab resistance by facilitating p27 degradation.
Jab1/CSN5 (c-Jun activation domain-binding protein 1) is over-expressed in 50% of primary and 90% of metastatic breast cancers, while its expression is low or absent in normal adult breast tissues. We previously identified that high expression of Jab1 is associated with shorter progression-free survival in breast cancer patients. In this study, our preliminary data showed that the knockdown of Jab1 sensitizes the breast cancer cells to trastuzumab treatment in a dose-dependent manner. Mechanistically, we found that Jab1 over-expression is significantly correlated with the activation of Akt pathway in Her2+ breast cancer cells and xenograft model. Interestingly, activated Akt, due to PTEN loss or PI3K activating mutation has been widely implicated in the potential mechanism to trastuzumab resistance. Therefore, our results suggest that targeting Jab1 overcomes the resistance to trastuzumab via interfering with PI3K/Akt pathway.
In general, our study identifies Jab1 as a novel contributor to trastuzumab resistance and elucidates its potential mechanisms of actions. The successful completion of the study can potentially be translated to the clinic for the benefit of patients refractory to the therapy. Also our study suggests Jab1 expression level can be used as a predictive marker for trastuzumab treatment.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-02.
Abstract P5-08-04: Overexpression of CXCR-4 confers trastuzumab resistance in human breast cancer cell lines
Authors: Mehta A , Wang-Kolodji GK , Tripathy D 
Published: August 2014

Abstract
Background: Trastuzumab significantly improves survival in patients with HER2 positive breast cancer; however, de novo or acquired resistance ensues in the advanced setting. We have identified differentially expression genes in acquired trastuzumab resistance cell line models following long-term trastuzumab exposure and have demonstrated consistent overexpression of CXCR-4 at the mRNA and protein levels. The interaction between the cognate ligand CXCL-12 and its receptor CXCR-4 is known to promote malignant cell proliferation and angiogenesis via activation of Akt and MAPK pathways. CXCR-4 shows no to low expression in normal breast epithelium while its expression sequentially increases from precancerous lesions to carcinomas. CXCR-4 overexpression in human breast cancer is also associated with a worse outcome in small studies. We sought to explore the role of CXCR-4 expression on trastuzumab drug responsiveness.
Methods: Trastuzumab-resistant cell lines were generated by serial passaging of HER+ cells lines BT-474 and SKBR-3 for 1 year with continual exposure to 200 μg/ml of trastuzumab. For these resistant cell lines, termed BtRT and SkRT, CXCR-4 mRNA was quantified using qRT-PCR, and CXCR-4 protein expression was quantified by Western blot. Stable clones overexpressing CXCR-4 receptor were selected by transfecting CXCR-4 sequence-containing lentivirus into sensitive parental sensitive BT-474 and SKBR3 cells. Expression of CXCR-4 receptor was assessed by Western blot assay and by flow cytometry. MTT cell viability analysis was performed on these transfected cell lines to characterize trastuzumab dose responsiveness with parental cells as control.
Results: Trastuzumab-resistant cell line BtRT demonstrated a 100-fold increase in IC50 to trastuzumab treatment when compared to parental BT-474 cells and also exhibited a 3-fold further increase in CXCR-4 mRNA and a corresponding increase in CXCR-4 protein. CXCR-4-transfected sensitive BT474 cell lines showed a greater than 100 fold increase in the IC50 value on MTT assay after treatment with trastuzumab as compared to the parental cell line. Semi-quantitative analysis by Western-blot confirmed a 5-fold increase in CXCR-4 expression in CXCR-4-transfected cells as compared to parental cells. CXCR-4 expression in HER2+ human breast tumors and responsiveness in patients treated with neoadjuvant trastuzumab-based therapy will be presented.
Conclusion: CXCR-4 overexpression and activation of the CXCR-4/CXCL-12 pathway contributes to trastuzumab resistance in human breast cancer cell lines. CXCR-4 targeting may represent a therapeutic strategy to improve the efficacy of trastuzumab in HER2-positive breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-04.
Abstract P5-08-10: Upregulation of microRNA-181a promotes metastasis of breast cancer cells following chemotherapy
Authors: Niu J , Shi Y , Wu Z-H 
Published: August 2014

Abstract
Recent studies indicated that genotoxic treatment may promote cancer cell invasion. Moreover, resistance to chemotherapy highly correlates with high metastatic potential in breast cancer patients. Nevertheless, the molecular mechanisms linking chemotherapeutic resistance to metastasis remain poorly understood. Here, we show that microRNA-181a (miR-181a) plays an important role in promoting chemodrug-induced breast cancer metastasis. Treatment with genotoxic drugs increases miR-181a expression in triple-negative breast cancer cells, which is dependent on NF-kB activation by DNA damaging agents. Genotoxic NF-κB activation upregulates IL-6 expression and secretion in breast cancer cells, which leads to STAT3 (signal transducer and activator of transcription 3) phosphorylation and activation. Activated STAT3 translocates onto miR-181a gene promoter region and enhances its transcription in response to genotoxic treatments. Interestingly, chemodrug treatment also induces epigenetic modifications, such as increased histone H3 Ser28 phosphorylation and decreased H3 Lys27 trimethylation, at miR-181a promoter region, which are also required for miR-181a up-regulation. In addition, we found overexpression of miR-181a in breast cancer cells significantly enhanced cell invasion and metastasis, while inhibiting miR-181a reduced cell aggressiveness upon genotoxic exposure. We further show that miR-181a directly suppresses the expression of ataxia telangiectasia mutated (ATM) in breast cancer cells, which plays a pivotal role in DNA damage response and cancer progression. Therefore, our findings support a critical role of DNA damage-induced miR-181a in promoting breast cancer metastasis following chemotherapeutic treatment. Further exploration of molecular mechanisms regulating miR-181a induction and miR-181a-driven aggressive behaviors of breast cancer cells in response to chemotherapy may reveal novel approaches to reduce metastasis and improve therapeutic response in breast cancers by targeting miRNAs.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-10.
Abstract P5-11-05: Overexpression of girdin in nucleus indicates poor disease-free survival in ER-positive breast cancer
Authors: Peng W-T , Hu X , Yao L , Jiang Y-Z , Yu K-D , Shao Z-M 
Published: August 2014

Abstract
Background
Girdin is identified as a novel modulator of the PI3K-Akt signaling pathway in regulating neurons integration during neurogenesis process. Recently, several studies demonstrated that Girdin and its phosphorylation type (p-Girdin) were also involved in tumor metastasis and angiogenesis. However, the clinical implications of Girdin and p-Girdin in breast cancer remain unclear. In this study, we detected the expression pattern of p-Girdin (Ser1416) and Girdin in breast cancer to uncover the association between p-Girdin/Girdin status and clinicopathological parameters like estrogen receptor (ER), progestogen receptor (PR), and human epidermal growth factor receptor 2 (Her2), etc.
Methods
This study included 250 patients who were histologically confirmed as invasive ductal breast cancer and underwent mastectomy in the Department of Breast Surgery in Shanghai Cancer Center during 2001 to 2006. We performed immunohistochemistry of p-Girdin/Girdin on tissue microarrays constructed from above specimens.
Results
We observed that Girdin was mainly located in the cytoplasm of mammary epithelial carcinoma cells (195/248, 78.63%) while p-Girdin was mainly located in the nucleus (160/250, 64.00%). However, Girdin/p-Girdin was also weakly expressed in the nucleus/cytoplasm (77/248, 31.05% for Girdin and 193/250, 77.2% for p-Girdin). By the Chi-square test, we found that Girdin in the nucleus (GN) was positively associated with ER status (P = 0.012); Girdin in the cytoplasm (GC) was positively associated with ER (P = 0.004), PR (P = 0.028), and Her2 status (P = 0.004); p-Girdin in the cytoplasm (pGC) was positively associated with PR status (P = 0.001) and negatively associated with tumor size (P = 0.025). However, no significant association was observed between p-Girdin in the nucleus (pGN) and other parameters. Using Kaplan-Meier method, we disclosed a trend that GN indicated poor disease-free survival (DFS) in ER-positive breast cancer (P = 0.075). After adjusted for histological grade and tumor size, multivariate cox regression analysis confirmed this trend (HR = 3.051, 95% CI: 1.137-8.191, P = 0.027). Furthermore, GC was prone to associating with poor DFS, especially in stage II (P = 0.079) and grade III (P = 0.058) patients.
Conclusions
Our work reveals, for the first time, that the location and expression pattern of both Girdin and p-Girdin (Ser1416) in breast cancer, suggesting that p-Girdin/Girdin are associated with ER, PR and Her2 status. In addition, Girdin in the nucleus is associated with poor DFS in ER-positive breast cancer.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-11-05.
Abstract P5-12-08: Survival differences by stage and race/ethnicity using the Nottingham prognostic index
Authors: Parise C , Caggiano V 
Published: August 2014

Abstract
Background
It is well documented that race/ethic disparities in breast cancer survival exist. The Nottingham Prognostic Index (NPI), based on tumor size, lymph node status, and histologic grade, is a well established method of predicting survival of operable breast cancer. The purpose of this investigation is to determine if race/ethnic disparities also exist among the NPI categories.
Method
We identified 157, 865 cases of stages 1-3 first primary female invasive breast cancer from the California Cancer Registry diagnosed between January 1, 2000 and December 31, 2010. The NPI was computed and cases were stratified as having good (NPI &lt;3.4), moderate (3.4-5.4) and poor (&gt; 5.4) prognosis. Kaplan Meier Survival analysis (95% CIs) was used to compare survival at eight years for patients who were white, black, Hispanic, or Asian/Pacific Islander (API) within each AJCC stage and NPI category.
Results
The distribution of cases by stage, race/ethnicity and good, moderate, and poor NPI categories is seen in the table.
Distribution of cases by stage, race/ethnicity and NPI categories WhiteBlackHispanicAPITotalStage 1 Good15,8287442,4432,16921,184Moderate28,9841,8025,1954,20040,181Poor9,7701,0152,4351,85515,075Stage 2 Good237234842350Moderate4,0872567315155,589Poor37,1094,00710,8937,18659,195Stage 3 Good803112Moderate56216983Poor9,4511,2793,7021,76416,196Total 157,865
Stage 1: There were no significant differences in survival within the good category. In the moderate category, APIs (95.5; 94.5, 96.6) had better survival than whites (93.6; 93.2, 94.0) whereas blacks (90.1; 87.8; 92.3) had worse survival. In the poor NPI category, APIs (92.6; 90.8, 94.4) also had better survival than whites (88.7; 87.8, 89.6).
Stage 2: In the moderate NPI category, blacks (92.8; 89.0, 96.7) had worse survival than whites (94.0; 93.0, 95.1) and in the poor category, blacks (73.8; 71.9, 75.8) and Hispanics (80.7; 79.5, 81.8) both had worse survival than whites (81.8; 81.2, 82.3) while APIs had better survival (84.6; 83.3, 85.8).
Stage 3: There were too few patients in the good and moderate NPI categories. In the poor category, blacks (47.8, 43.4, 52.1) had worse survival than whites (60.1; 58.4, 61.8) while APIs (64.2; 60.2, 68.2) had better survival.
Conclusion
The NPI provides further refinement of the disparities in survival among race/ethnicity. It appears that APIs have better survival than whites in all stages of disease.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-08.
Abstract P5-12-10: Pathological characteristics and patterns of recurrence and mortality among young Mexican breast cancer patients
Authors: Villarreal-Garza CM , Hoyos CM , Meza-Herrera V , Palacios VA , Hernandez-Vega MB , Aguila C , Lara-Medina F , Meneses A , Mohar A 
Published: August 2014

Abstract
Background: In Mexico, it is recognized that breast cancer (BC) is diagnosed at younger ages than that reported in the US and other populations. Although national data is not available regarding BC age of diagnosis distribution, data from the INCAN, the main referral center in Mexico, showed that 17% of the total 893 newly diagnosed BC patients seen in 2012 were younger than 40 years old (which is more than twice that -7%- reported for US BC patients). We conducted a retrospective study in order to describe the frequency of BC among young Mexican BC patients, as well as their pathological characteristics at diagnosis and patters of recurrence.
Methods: Clinical and pathologic data from young pts (≤42 years old) who were newly diagnosed with invasive BC between January 2007 and December 2010 at the INCAN in Mexico and were followed for at least 2 years were identified. Clinical stage at diagnosis was recorded and estrogen receptor, progesterone receptor and HER2 expression were determined by immunohistochemistry and/or FISH. Proportion differences were tested using the Chi-square test.
Results: 445 young patients were identified from a total of 2919 BC patients (15%). A total of 320 patients met the inclusion criteria for analysis. Median age of diagnosis was 36 years (19-42). 49% of patients were very young patients (≤ 35 years). 19% were diagnosed as early disease, 67.5% as locally advanced BC and 13.5% as metastatic. 32% of patients had triple negative BC disease, while 27% were HER2 positive. From the non-metastatic patients at diagnosis, 31% developed recurrence (65% systemic, 21% loco regional and 14% both). After a median follow-up of 26 months, 18% of the 320 patients died secondary to BC disease progression.
Conclusions: Although this series corresponds to patients treated at a reference national center, the data reported in this study suggests that BC among young women is very prevalent in Mexico compared to other populations. The causes underlying the striking difference in age at diagnosis in Mexican BC patients are unknown and have not been investigated, including the genetic contributing factors. As reported in non-Hispanic population studies, BC among young women is diagnosed in more advanced stages, and triple-negative and HER2 positive diseases are more frequent. It is associated with a high proportion of systemic and loco regional recurrence, with a dismal prognosis. Due to the substantial number of BC cases among young women in Mexico, its prospective study is more than justified. In order to meet with this goal, our group is preparing the establishment of the Mexican Young Women's Breast Cancer Cohort Program at the INCAN in Mexico and to launch the related scientific projects related to this plan.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-10.