bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-06-18: Targeting basal-like breast cancer through downstream effectors of oncogene cooperation
Authors: McMurray HR , Walters EA , Heyer DM , Candelaria PV , Wang S , Grose VA , Llop JR , Zhang Y 
Published: August 2014

Abstract
Basal-like breast cancer is a highly aggressive and lethal form of cancer, not amenable to treatment by molecularly targeted agents or conventional chemotherapy effective against other forms of breast cancer. Thus, discovery of novel intervention targets regulating tumorigenesis in basal-like breast cancer cells is critical. The success of molecularly targeted therapies against some forms of cancer has led to a search for additional cancer cell-specific targets that will permit effective tumor inhibition with minimal damage to normal cells. These efforts are largely focused on identification of novel oncogenes and tumor suppressors by genome sequencing or synthetic lethalities found via genome-wide RNAi screens. We employ a novel approach to identify cancer cell vulnerabilities among genes disregulated downstream of cooperating oncogenic mutations, which drive malignant transformation in large part through synergistic modulation of non-mutated downstream effector genes, the ‘cooperation response genes’ (CRGs) [McMurray et al., Nature, 19 June 2008]. After assessing how common was CRG disregulation in different epithelial cancers, via comparative genomic analysis of CRG expression patterns in tumor vs. normal tissue, we found that 34 CRGs (∼35%) were significantly disregulated in breast cancer. Because of the need for novel intervention targets in basal-like breast cancer, we focused our functional analysis there. We have tested a subset of CRGs disregulated in breast tumors for their contribution to malignancy in basal-like breast cancer cells, re-setting CRG levels toward normal cell levels by stable cDNA expression or shRNA-mediated knock-down and testing tumor formation capacity of perturbed cells. Our studies reveal that CRGs play an essential role in controlling tumor formation of basal-like breast cancer cells, with significant reductions in tumor volume, and in some cases reduced tumor incidence, upon CRG modulation. Disruption of cell behavior appears to be limited to cancer cells, as non-transformed mammary cells harboring analogous perturbations retain capacity to form acinar structures in 3D culture. Several FDA approved pharmacological agents, identified to reverse the CRG expression pattern, display inhibitory effects on basal-like breast cancer cell lines, with minimal effects on non-transformed cells. CRGs thus represent cancer cell-specific vulnerabilities in basal-like breast cancer, providing novel and unexpected opportunities for intervention against this difficult-to-target disease.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-18.
Abstract P4-07-02: Growth differentiation factor 15, a novel mediator of progression in HER2-positive breast cancer
Authors: Nahta Rita , Joshi Jayashree P , Griner Samantha E , Adams Amy L , Andre Fabrice 
Published: August 2014

Abstract
Withdrawn by Author
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-07-02.
Abstract P4-07-03: Rapamycin and Dalotuzumab in combination inhibit parental and endocrine resistant breast cancer cells.
Authors: Beckwith H , Fettig-Anderson L , Yueh N , Douglas Y 
Published: August 2014

Abstract
The PI3K/Akt/mTOR pathway is involved in breast cancer resistance to endocrine therapy. Inhibitors of mTOR have been shown to have benefit for patients with ER positive tumors that have developed endocrine therapy resistance. Inhibition of mTOR triggers a negative feedback loop resulting in enhanced phosphorylation of Akt and subsequent breast cancer cell proliferation via the IGF signaling pathway. Therefore, blockade of both IGF-1R and mTOR may be necessary to completely suppress this pathway. Our laboratory studied the effect of dual inhibition of mTOR and IGF-1R with rapamycin and dalotuzumab respectively on parental and endocrine resistant MCF-7 breast cancer cell tumorigenesis.
Immunoblotting demonstrates parental MCF-7L cells treated with rapamycin alone demonstrate increased phosphorylation of Akt. Inhibition of phosphorylation of Akt can be achieved with combined treatment with rapamycin and dalotuzumab at concentrations of 5 nM and 2 µg/mL respectively. In addition to inhibition of pAkt, combined treatment inhibits phosphorylation of S6K1 and the translational repressor protein, 4eBP1. Furthermore, MTT proliferation assay and soft agar assay demonstrate inhibition of parental cell proliferation and colonization respectively with combined rapamycin and dalotuzumab treatment. In order to examine the effect of combination therapy in endocrine resistant cell lines, we established tamoxifen resistant (TamR) and long term estrogen deprived (LTED) cell lines. TamR cells were generated by culturing MCF-7L cells in the presence of tamoxifen for more than 1 year. LTED cells were generated by culturing MCF-7L cells in the absence of estrogen for more than 6 months. Proliferation of TamR and LTED cells treated with rapamycin at a concentration of 5nM and dalotuzumab at a concentration of 2µg/mL in combination was significantly inhibited. We conclude that combination of IGF1R and mTOR inhibition might be necessary to inhibit endocrine resistant breast cancers. Ongoing clinical trials will test this combination of drugs.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-07-03.
Abstract P4-07-05: MEDI3379, an antibody against HER3, is active in HER2-driven human breast tumor models
Authors: Xiao Z , Rothstein R , Carrasco R , Wetzel L , Kinneer K , Chen H , Tice D , Hollingsworth R , Steiner P 
Published: August 2014

Abstract
HER3 (ERBB3) is a member of the EGFR/HER family of receptor tyrosine kinases (RTK), consisting of EGFR, HER2, HER3 and HER4. Unlike the other HER family members, HER3 lacks intrinsic tyrosine kinase activity and therefore needs to form heterodimers with EGFR, HER2 or other kinase-proficient RTKs to be functionally active. Dimerization is induced by overexpression of EGFR or HER2 in a ligand-independent (LI) manner. In this process HER3 acts as a driver in divergent cancer types including HER2-positive breast cancer (BC) via induction of the PI3K-AKT pathway. Alternatively, heregulin (NRG1/HRG), the major HER3 ligand, induces a conformational shift in HER3 which leads to dimer formation with a partner RTK in a ligand-dependent (LD) manner.
We have developed an antagonistic human monoclonal antibody against HER3, termed MEDI3379, and tested it in multiple breast cancer cell lines. We observed effective suppression of constitutive pHER3 and pAKT with MEDI3379, leading to anti-proliferation effects in cell culture models. Preclinical evaluation of MEDI3379 demonstrated antitumor activity in several orthotopic BC xenografts in nude mice which did not express HRG. For example, the BC xenograft model BT474 with amplified HER2 responded to MEDI3379 (65% dTGI). In conclusion, our findings with targeting of HER3 in mouse models support continued development of MEDI3379 for cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-07-05.
Abstract P4-08-02: Reactivation of oncogenic signaling through mTOR inhibitors-induced feedback adaptations.
Authors: Rodrik-Outmezguine V , Chandarlapaty S , Poulikakos P , Scaltriti M , Baselga J , Rosen N 
Published: August 2014

Abstract
mTORC1 inhibitors (or rapalogs) relieve feedback inhibition of receptor tyrosine kinases (RTKs) and cause mTORC2-dependent phosphorylation of AKT S473 and activation of AKT kinase and signaling. The relief of feedback inhibition of mTORC2/AKT signaling has been shown to abolish the antitumor activity of rapalogs and has often been proposed as a potential mechanism of resistance to these compounds.
mTOR kinase inhibitors that inhibit both mTORC1 and mTORC2 complexes have now been developed to circumvent these problems. mTOR kinase inhibitors block mTORC1 and mTORC2 and thus, do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these novel classes of drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT S473 dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase, as observed with rapalogs, also relieves feedback inhibition of RTKs leading to subsequent PI3K activation and rephosphorylation of AKT but only at T308, which is sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound inhibition of mTORC1 and accumulation of activated AKT phosphorylated on T308 but not S473.
We now confirm that the reactivation of AKT signaling is a mechanism of acquired resistance to rapalogs. We observe an induction of phospho-RTKs in rapamycin-resistant cells leading to both AKT and ERK signaling pathway activation enhancing cell survival. Combined inhibition of mTOR and the induced RTKs can prevent AKT reactivation and fully abolishes AKT signaling. These results reveal the adaptive capabilities of oncogenic signaling networks, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-02.
Abstract P4-08-06: Notch-dependent Regulation of Novel Genes Associated with Trastuzumab Resistance
Authors: Osipo C , Baumgartner A , Zlobin A , O'Toole M 
Published: August 2014

Abstract
Background: We have shown previously that Notch-1 is critical for the development and maintenance of trasuzumab or lapatinib resistance in HER2 positive breast cancer cell lines. Here we sought to identify the critical genes that are regulated by Notch to promote anti-HER2 targeted resistance.
Methods: We measured expression of 84 known breast cancer-associated transcripts using a real-time PCR array in both trastuzumab sensitive and resistant BT474 cell lines. A 4 fold increase or decrease in transcripts levels were measured to be statisitically significant. To confirm the change in levels, we designed primers to each gene of interest and repeated the PCR at least three independent times. Furthermore, we specifically asked whether Notch-1 or it's transcriptional mediator, CBF-1, directly regulated any of the identified genes in HER2 positive breast cancer cells using a genetic knocked down approach. An ANOVA for multiple comparisons was used to compute statistical significance.
Results: We identified more than 4 fold increase in APC, ABCG2, ABCB1, Gata-3, Bcl-2, Id2, and HRG-2 transcripts in trastuzumab resistant versus sensitive cells. Conversley, Gli1 was downregulated in resistant versus sensitive cells. Interestingly, siRNA directed against Notch-1 or CBF-1 decreased ABCG2 and Gata-3, but conversely increased ABCB1 and HRG-2 in resistant cells.
Conclusions: Our findings demonstrate APC, ABCG2, ABCB1, Gata-3, Bcl-2, Id2, and HRG-2 transcripts are signficantly increased in trastuzumab resistant breast cancer cells compared to sensitive cells. More importantly, Notch-1 or it's direct transcriptional activator CBF-1 may contribute to traztuzumab resistance by directly regulating critical genes that contribute to multidrug resistance: ABCB1 and ABCG2 and/or genes associated with stem cell survival: Gata-3 and HRG-2.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-06.
Abstract P4-08-09: Targeting Thyroid Receptor b in Estrogen Receptor Negative Breast Cancer
Authors: Gu G , Covington K , Rechoum Y , O'Malley B , Mangelsdorf D , Minna J , Webb P , Fuqua S 
Published: August 2014

Abstract
Background: The treatment of estrogen receptor (ER)-negative breast cancer (BC) is a major clinical problem due to the lack of useful therapeutic targets. Nuclear receptors (NRs) are potential targets in these patients because they regulate global transcriptional events and many already have agonists/antagonists available.
Material and Methods: We used microarray analysis of 227 ER-negative tumors to identify NR targets, and performed hierarchical clustering using 41 NRs. Expressed receptors were scored using prediction analysis of microarrays (PAM) across clustered groups. Cell lines were matched to subtypes using previously described data (Neve et al. 2006). Candidate gene expression levels were confirmed by qRT-PCR using TaqMan probes. pGIPZ lentiviral vectors encoding shRNA were used to knockdownselected candidates. MTT and soft agar assays were used to measure chemosensitivity and growth following treatment with Docetaxel (Doc), Doxorubicin (Dox), or Cisplatin (Cis). Statistical analysis was performed using Red-R.
Results: The 41 NRs clustered tumors into 5 groups. For each group we selected genes representing the highest ranked discriminators, and examined their effects in cell lines matching each groups' gene signature. Thyroid hormone receptor b (THRβ) was selected from group V. The expression levels of this receptor were confirmed by qRT-PCR and Western blot analysis.
Knockdown of THRβ in ER-negative HCC2185 cells rendered cells more resistant to all chemotherapeutics by using MTT assay. Similar results were confirmed in ER-negative MDA-MB-453 and HCC202 cells. Knockdown of THRβ enhanced colony forming potential in anchorage-independent soft agar assays in MDA-MB-453 and HCC202 cells. Statistical analysis using clinical data from Sabatier et al. (BCRT 2011) showed that patients with low THRb have a worse clinical outcome. In order to translate these findings into the clinic, we treated cells with a specific THRβ agonists, GC-1 and KB-141. GC-1 inhibited cell growth in growth assays, and synergistic effects were observed when cells were treated with GC-1 and Docetaxel in combination. Re-expression of ERα protein was observed in ER-nagative cells lines after treatment with GC-1 and KB141, suggesting that modulation of THRβ may also extend hormonal therapy to this hormonally insensitive group of patients.
Conclusion: Clinical targeting of NRs in ER-negative BCs is a novel strategy since receptors can be specifically targeted with ligands. Our data suggest that chemotherapy response in ER-negative patients overexpressing THRβ could be enhanced with a THRβ agonist. Similarly, functional re-activation of ERα by activating THRβ might extend hormonal therapies to these patients as well.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-08-09.
Abstract P4-09-03: Comparative proteomic analysis identifies a 15-protein signature related to clinical outcome of triple negative breast cancer
Authors: Liu Ning Qing , De Marchi Tommaso , Stingl Christoph , Timmermans Annemieke M , Look Maxime P , Braakman René BH , Smid Marcel , Foekens Renée , Trapman Anita MAC , Luider Theo M , Martens John WM , Foekens John A , Umar Arzu 
Published: August 2014

Abstract
Withdrawn by Author
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-03.
Abstract P4-09-04: Gene expression profile that predict outcome of Tamoxifen-treated estrogen receptor-positive, high-risk, primary breast cancer patients: a DBCG study.
Authors: Lyng MB , Lænkholm A-V , Tan Q , Vach W , Gravgaard KH , Knoop A , Ditzel HJ 
Published: August 2014

Abstract
Background: Tamoxifen significantly improves outcome for estrogen receptor-positive (ER+) breast cancer, but the 15-year recurrence rate remains 30%. The aim of this study was to identify gene profiles that accurately predicted the outcome of ER+ breast cancer patients who received adjuvant Tamoxifen mono-therapy.
Methods: Post-menopausal breast cancer patients diagnosed no later than 2002, being ER+ as defined by &gt;1% IHC staining and having a frozen tumor sample with &gt;50% tumor content were included. Tumor samples from 108 patients treated with adjuvant Tamoxifen were analyzed for the expression of 59 genes using quantitative-PCR. End-point was clinically verified recurrence to distant organs or ipsilateral breast. Gene profiles were identified using a model building procedure based on conditional logistic regression and leave-one-out cross-validation, followed by a non-parametric boostrap (1000x re-sampling). The optimal profiles were further examined in 5 previously-reported datasets containing similar patient populations that were either treated with Tamoxifen or left untreated (N = 623).
Results: Three gene profiles were identified, the strongest being a 2-gene combination of BCL2-CDKN1A exhibiting an accuracy of 75% for prediction of outcome. Independent examination using 4 previously-reported microarray datasets of Tamoxifen-treated patient samples (N = 503) confirmed the potential of BCL2-CDKN1A (average accuracy: 68%, range: 53%–85%). The predictive value was further determined by comparing the ability of the genes to predict recurrence in an additional, previously-published, cohort consisting of Tamoxifen-treated (n = 58, p = 0.015) and untreated patients (n = 62, p = 0.25).
Conclusion: A novel gene expression profile predictive of outcome of Tamoxifen-treated patients was identified. The validation suggests that BCL2-CDKN1A exhibit strong predictive potential.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-09-04.
Abstract P4-11-02: Novel BRCA1 and BRCA2 genomic rearrangements in Southern Chinese breast/ovarian cancer patients
Authors: Kwong A , Ng EKO , Law FBF , Wa A , Wong CLP , Wong CHN , Kurian AW , West DW , Ford JM , Ma ESK 
Published: August 2014

Abstract
Background and Aims: Germline mutations in the two breast cancer susceptibility genes, BRCA1 and BRCA2 account for a significant portion of hereditary breast/ovarian cancer. Most of the BRCA mutations reported in Southern Chinese patients were point mutations, small deletions, and insertions. The spectrum of large genomic rearrangement (LGR) is largely unknown. Here we perform the first study on the LGR of BRCA genes in a Hong Kong Chinese population. We aimed to determine the spectrum of BRCA LGRs in Southern Chinese patients with breast cancer.
Methods: A total of 555 clinically high-risk breast and/or ovarian cancer patients were recruited from the Hong Kong Hereditary Breast Cancer Family Registry, diagnosed from March 2007 to November 2011. Multiplex ligation-dependent probe amplification (MLPA) for detecting BRCA LGRs together with comprehensive BRCA1 and BRCA2 gene sequencing of all coding exons were performed. cDNA sequencing of the LGRs was performed to locate the breakpoint of the deletions.
Results: Overall BRCA1/2 mutation prevalence among this cohort was 12.4% (69/555). Among the 69 mutations identified, 4 novel LGRs (2 in BRCA1 and 2 in BRCA2) were detected only by MLPA but not full gene sequencing. Overall the LGR genes accounted for 5.8% (4/69) of all BRCA mutations in our cohort, 6.9% (2/29) of all BRCA1 mutations and 5% (2/40) of all BRCA2 mutations.
Conclusions: These findings highlight the LGR spectrum of BRCA1 and BRCA2 genes in Southern Chinese breast cancer patients. LGR testing together with BRCA1/2 full gene sequencing is superior to other methods for comprehensive BRCA1/2 analysis in clinical settings.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-11-02.
Abstract P4-11-03: Single nucleotide polymorphism testing for breast cancer risk assessment: patient trust and willingness to pay
Authors: Howe R , Omer Z , Hanoch Y , Miron-Shatz T , Thorsen C , Ozanne EM 
Published: August 2014

Abstract
Background: The field of breast cancer risk assessment is advancing rapidly with recent discoveries about risk conferring single nucleotide polymorphisms (SNPs). While these discoveries can promote personalized medicine, they are often brought to the market with direct to consumer (DTC) testing before data can support their widespread use and before reliable options for dealing with testing outcomes can be offered. In this context, and knowing that patients often misunderstand risk information, it is unclear how patients will respond to these options.
Methods: We surveyed high risk women's interest in SNP testing. Participants were recruited from the Cancer Genetics Network (CGN), a national network of cancer centers that maintains a database of individuals with a family history of cancer. Participants were asked to answer questions regarding their interest in SNP testing including: whether they trust it, how much they would be willing to pay for testing, how they prefer to be tested, and how they would proceed with information identifying them as below or above average risk.
Results: 189 women without a history of breast cancer or SNP testing completed the questionnaire. The average age of the participants was 49, ranging from 30 to 65. All participants had at least one relative with breast or ovarian cancer. 13% had previously tested positive for a BRCA mutation, and 33% had received BRCA testing. Most women (90%) did not know what SNP testing was prior to the survey. Once SNP testing was described, 68% of women were interested in DTC SNP testing; at the same time, only 38% of the participants reported that they trusted DTC SNP testing.

Conclusion: While our results show that women are interested in DTC SNP testing, their willingness to pay is lower than the DTC cost (∼$300). Involvement of genetic counselors and providers in SNP testing discussions may be needed to overcome the current lack of trust of DTC testing among patients. Many women showed interest in lifestyle interventions, suggesting that these interventions should be incorporated as part of standard follow-up recommendations. When identified by SNP testing as “below average” risk, women do not seem to trust the results enough to forego regular mammograms. As DTC testing becomes more common, and as more SNP tests become available, it will be necessary for the medical community to address patients' interest in these tests and to assist in interpreting results.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-11-03.
Abstract P4-11-05: Optimal age to start preventive measures in women with BRCA1/2 mutations or high familial breast cancer risk
Authors: Tilanus-Linthorst MMA , Lingsma H , Evans GD , Kaas R , Manders P , Hooning MJ , van Asperen CJ , Thompson D , Eeles R , Oosterwijk JC , Leach MO , Steyerberg EJ 
Published: August 2014

Abstract
Background: Women from high risk breast cancer families consider preventive measures including screening. Guidelines on screening differ considerably regarding starting age. We investigated whether age at diagnosis in affected family members is predictive for age at diagnosis of a relative.
Methods: We analyzed the age of breast cancer detection of 1304 first and second degree relatives of 314 BRCA1, 164 BRCA2 and 244 high-risk participants of the Dutch MRI-SCreening study. The within and between family variance in age at diagnosis was analyzed with a random effect linear regression model. We compared the starting age of screening based on risk-group (25 years for BRCA1, 30 years for BRCA2 and 35 years for familial risk), on family history, and on the model, which combines both. The findings were validated in 63 families from the UK- MARIBS study.
Results: Mean age at diagnosis in the family varied between families; 95% range of mean family ages was 35–55 in BRCA1−, 41–57 in BRCA2− and 44–60 in high-risk families.14% of the variance in age at diagnosis was explained by family history, 7% by risk group.
Approaches to determining start of screening based on the model and on risk-group were similar in terms of cancers missed and years of screening. The approach based on familial history only, missed more cancers and required more screening years in both the Dutch and UK datasets.
Conclusion: Age at breast cancer diagnosis is in part dependent on family history which may assist planning starting age for preventive measures.
Keywords: BRCA1, BRCA2, breast cancer, prevention, age at onset
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-11-05.