bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-04-17: The androgen metabolite-dependent growth in hormone receptor positive breast cancer as a novel aromatase inhibitor-resistance mechanism
Authors: Hanamura T , Niwa T , Nishikawa S , Konno H , Ghono T , Kobayashi Y , Kurosumi M , Takei H , Yamaguchi Y , Ito K-I , Hayashi S-I 
Published: August 2014

Abstract
Introduction: Aromatase inhibitors (AIs) have been reported to exert their anti-proliferative effects not only by reducing the production of estrogens but also by unmasking the inhibitory effect of androgens such as testosterone (TS) or dihydrotestosterone (DHT) in postmenopausal women with hormone receptor-positive breast cancer. The behavior of androgens in AI-resistance mechanisms is not sufficiently understood. 5α-androstane-3β,17β-diol (3β-diol) generated from DHT by 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD type 1: HSD3B1) has androgenic activity and substantial estrogenic activity, representing a potential mechanism of AI resistance.
Methods: To investigate these issues, ERE-GFP-transfected MCF-7-E10 cells were cultured for 3 months under steroid-depleted, TS-supplemented conditions which is the similar as the AI treatment. Among the surviving cells, two stable variants that show ER activity depending on androgen metabolites were selected as AD-EDR (androgen metabolite-dependent and estrogen depletion-resistant) by monitoring GFP expression. Using these cell lines, we investigated the process of adaptation to androgen-abundant conditions and the role of androgens in AI-resistance mechanisms.
Results: AD-EDR cell lines showed increased growth and induction of estrogen-responsive genes rather than androgen-responsive genes by androgens or 3β-diol. Further analysis revealed increased expressions of HSD3B1 and reduced expression of androgen receptor (AR) in these cell lines. In parental MCF-7-E10 cells, ectopic expression of HSD3B1 or inhibition of AR resulted in adaptation to estrogen-deprived and androgen-abundant conditions. In coculture with stromal cells replicating the local estrogen production from androgen, AD-EDR cell lines showed AI resistance compared with parental MCF-7-E10 cells. Immunohistochemistry and real-time PCR analyses on 9 pairs of primary and recurrent tissue samples from AI-resistant breast cancer revealed the decrease of AR protein expression in all cases and increase of HSD3B1 mRNA expression in 5.
Conclusion: In the present study, we successfully cloned two stable variants that show ER activity depending on androgen metabolites. Investigation of these cell lines suggested that the increased function of 3β-HSD type 1 and reduced function of AR contribute to AI resistance by enhancing the androgen metabolite-dependent growth and reducing the inhibitory effect of androgens. Our data of clinical samples suggest that this mechanism also acts as an AI-resistance in clinical breast cancer in some cases.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-17.
Abstract P6-04-26: Tamoxifen may block estrogen induced secretion of certain cytokines to interrupt tumor associated macrophage infiltration in breast cancer
Authors: Ding J , Chen CM , Jin W , Shao Z , Wu J 
Published: August 2014

Abstract
The role of tumor microenvironment during the initiation and progression of breast cancer is now realized to be of critical importance, both for understanding of the fundamental cancer biology and exploiting relatively new mechanism for breast cancer metastasis. Macrophage is a one of the most common components in the breast cancer microenvironment. Normally, the macrophage in tumor microenvironment is referred to tumor associated macrophage (TAM), which shares some attributes of alternatively activated macrophage. Many pre-clinical and clinical studies demonstrate an inverse correlation between TAM infiltration and patients' prognosis indicating a macrophage supporting role for tumor progression. It is well documented that selective patients with breast cancer can benefit from anti-estrogen therapy. However, the mechanisms involved are still not fully elucidated. Our previous study indicates that highly tumorigenic breast cancer cell line MDA-MB-231 can educate monocyte differentiation into alternatively activated macrophage, while weakly tumorigenic cell line MCF-7 (without estrogen supplementation) can not. In the present study, we explored the effects of estrogen and tamoxifen on the secreting of certain cytokines, which are required for monocyte chemotaxis and differentiation. Breast cancer cell lines with different estrogen receptor status were applied to estimate the level of cytokines (IL4, IL6, M-CSF, GM-CSF, and MCP-1) before and after cultured with 17β-estradiol, tamoxifen or both. We found that weakly invasive breast cancer cell lines (MCF-7, T47D, MDA-MB-468, and SKBR3) generally expressed lower levels of such cytokines compared with highly invasive breast cancer cell lines (MDA-MB-231, MDA-MB-231-BO, MDA-MB-231 HM, Bcap 37, BT549, and Hs578T) at baseline. However, the discrepancies could be compensated partially by exposure to 10nM 17β-estradiol in estrogen receptor (ER) positive cell lines (MCF-7 and T47D). Moreover, the compensation was substantially blocked by 2μM tamoxifen. On the contrary, tamoxifen, alone, didn't affect the secretion of such cytokines mentioned above in vitro. Based on these findings, we tentatively concluded that some patients with ER positive breast cancers benefiting from anti-estrogen therapy may partially attributes to blocking monocyte differentiation into TAM, which destroyed the tumor microenvironment. These findings suggest the future possibility of using TAM as a novel therapeutic target in patients with anti-estrogen resistance and primary triple-negative breast cancers (TNBC) with no effectively therapeutic measures nowadays, which are defined by lack of estrogen receptor, progesterone receptor and ERBB2 gene amplification, representing approximately 16% of all breast cancers.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-26.
Abstract P6-04-29: Vitamin D induces expression of estrogen receptor and restores endocrine therapy response in estrogen receptor-negative breast cancer
Authors: Santos N , Diaz L , Ordaz D , Garcia J , Barrera D , Avila E , Halhali A , Medina H , Camacho J , Larrea F , Garcia R 
Published: August 2014

Abstract
Background: Approximately 30% of all breast tumors do not express estrogen receptor (ER) and patients with these tumors present poor prognosis and respond poorly to hormone therapy. Calcitriol through its vitamin D receptor (VDR) exerts antiproliferative, apoptotic and pro-differentiating effects in cancer. Calcitriols effects upon ER expression in breast cancer cells is controversial. Therefore, in order to clarify this issue, the aim of the present study was to determine if calcitriol induces ERα expression in ERα-negative breast cancer cells and could restore antiestrogen responses. The evaluation of calcitriol effects was performed in terms of proliferation and regulation of the following genes: Cyclin D1, involved in cell cycle, and Ether-à-go-go 1 (Eag1), related to cell proliferation and tumor progression.
Methods: Cultured cells derived from ERα-negative breast tumors and an established ERα-negative breast cancer cell line (SUM 229) were used in this study. These cells were treated with calcitriol and reverse transcription-PCR or western blotting analyses were performed to assess ERα expression. Growth assays with XTT were used to evaluate the antiproliferative response to the antiestrogens fulvestran and tamoxifen. Gene expression analysis for Cyclin D1 and Eag1 was evaluated by real time PCR in cells treated simultaneously with calcitriol plus estradiol or fulvestran.
Results: The treatment with calcitriol in ER-negative breast cancer cells resulted in the induction of ERα. This effect was specifically mediated through the vitamin D3 receptor (VDR), since the VDR antagonist TEI-9647 effectively inhibited the ability of calcitriol to stimulate ERα gene expression. Consequently, the induction of ERα by calcitriol restores the response to antiestrogens in breast cancer cells by inhibiting cell proliferation. Co-treatment of calcitriol and antiestrogens down-regulated Cyclin D1 and Eag1 gene expression.
Conclusion: Calcitriol induced the expression of ERα and restored antiestrogenic responses in ERα-negative breast cancer cells. Moreover, fulvestran down regulated mRNA expression of Cyclin D1 and Eag1 when ERα-negative cells were pre-treated with calcitriol. These results suggest that the combined treatment with calcitriol and antiestrogens could be a new therapeutic strategy for ERα-negative breast cancer patients.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-29.
Abstract P6-05-07: Amplified in breast cancer 1 and ankyrin repeat containing cofactor 1 mediate estrogen induced repression of the ErbB2 oncogene
Authors: Garee JP , Riegel AT 
Published: August 2014

Abstract
The oncogene amplified in breast cancer 1 (AIB1/SRC3) is a nuclear receptor coactivator and plays an important role in the regulation of gene transcription. Additionally, AIB1 is important in malignant progression as AIB1 has been shown to be a gene amplified in breast cancer and is also over-expressed in a variety of cancer types. Previous work from our laboratory has identified a splice variant of AIB1 termed AIB1-Δ4. This splice variant arises from the splicing of exon 4 from the mature mRNA. This leads to the formation of an N terminally truncated form of the AIB1 protein, which is a more potent coactivator of steroid dependent transcription compared to the full length AIB1. This suggests that the N-terminal fragment of AIB1, which is not present in AIB1-Δ4, may act to dampen AIB1 mediated transcriptional activation. The presence of this N terminal region suggests this region may be a site of interaction with a repressive protein, which could interact with AIB1 and not AIB1-Δ4. We have identified ANCO1 as an N terminal AIB1 binding protein that acts to repress AIB1 mediated transcriptional activity. Co-immunoprecipitation experiments have indicated interaction between AIB1 and ANCO1 but not between AIB1-Δ4 and ANCO1 indicating ANCO1 binds in the N terminal region of AIB1. AIB1 has a clinical implications and association with the oncogene ErbB2, which is an estrogen repressed gene with hormone effect acting through an estrogen response element (ERE) in intron 1 of the ErbB2 gene. We wanted to determine if the AIB1/ANCO1 complex played a role in hormone regulation of ErbB2. Silencing of AIB1 and ANCO1 by shRNA led to a reversal of estrogen-induced repression of ErbB2 indicating this protein complex may play a role in mediating this repression. Examining binding of these proteins to the intronic ERE of ErbB2 we determined that AIB1 and ANCO1 are recruited in the presence of estrogen. Additionally, repressive proteins such as HDAC3, HDAC4 and N-CoR are recruited along with the AIB1/ANCO1 complex. While AIB1-Δ4 can still be recruited to the intronic ERE no additional repressive proteins are recruited. This suggests a mechanism by which the AIB1/ANCO1 complex can recruit repressive proteins to repress ErbB2 gene transcription, while AIB1-Δ4 can escape this repressive mechanism. This may potentially have interesting clinical implications, as high levels of AIB1-Δ4 may be responsible for increasing the expression levels of the ErbB2 oncogene.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-07.
Abstract P6-05-14: Estrogen-induced genes in ductal carcinoma in situ(DCIS): their comparison with invasive ductal carcinoma.
Authors: Ebata A , Suzuki T , Takagi K , Miki Y , Onodera Y , Nakamura Y , Fujishima F , Ishida K , Watanabe M , Tamaki K , Ishida T , Ohuchi N , Sasano H 
Published: August 2014

Abstract
It is well known that estrogens play important roles in both the pathogenesis and development of invasive ductal carcinoma (IDC) of human breast. However, molecular features of estrogen actions have remained largely unclear in pure ductal carcinoma in situ (pDCIS), regarded as a precursor lesion of many IDCs. This is partly due to the fact that gene expression profiles of estrogen-responsive genes have not been examined in pDCIS. Therefore, we first examined the profiles of estrogen-induced genes in estrogen receptor (ER)-positive pDCIS and DCIS (DCIS-c) and IDC (IDC-c) components of IDC cases (n = 4, respectively) by microarray analysis. Estrogen-induced genes identified in this study were tentatively classified into three different groups in the hierarchical clustering analysis, and 33% of the genes were predominantly expressed in pDCIS rather than DCIS-c or IDC-c cases. Among these genes, the status of MYB (c-MYB), RBBP7 (RbAp46) and BIRC5 (survivin) expression in carcinoma cells was significantly higher in ER-positive pDCIS(n = 53) than that in ER-positive DCIS-c (n = 27) or IDC-c (n = 27) by subsequent immunohistochemical analysis of the corresponding genes (P &lt; 0.0001, P = 0.03 and P = 0.0003, respectively). In particular, the status of c-MYB immunoreactivity was inversely (P = 0.006) correlated with Ki-67 in the pDCIS cases. These results suggest that expression profiles of estrogen-induced genes in pDCIS may be different from those in IDC, and c-MYB, RbAp46 and survivin may play particularly important roles among estrogen induced genes in ER-positive pDCIS.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-14.
Abstract P6-06-02: Characterization of an exosome-associated apoptosis-inducing activity produced by triple negative breast cancer cells.
Authors: Georgoulia NE , Iliopoulos D , Mitchison TJ 
Published: August 2014

Abstract
Purpose: We sought to investigate whether breast cancer cells can suppress the proliferation of other breast cancer cells in order to understand the biological significance of cell heterogeneity in breast cancer.
Materials and Methods: 20 breast cancer cell lines, corresponding to all molecular profiles of breast cancer, were cultured in a 20×20 conditioned medium protocol. Cell proliferation and apoptosis were evaluated by EdU (5-ethynyl-2′-deoxyuridine) and PARP (Poly ADP ribose) cleaved labeling respectively, and documented by fluorescence microscopy. Serum free conditioned media (CM) were prepared from all the cell lines, 24hrs of incubation, and screened for their anti-proliferative effect against the different breast cancer tumor cells. Active media were ultra-centrifuged and both the supernatants as well as the pellets were assessed for the anti-proliferative activity.
Results: Using this 20×20 matrix, CM obtained from two out of six triple negative breast cancer cells displayed anti-proliferative activity against the majority of cell lines, irrespectively of their molecular phenotype including triple negative cells. No significant anti-proliferative activity was observed in CMs from luminal or HER2(+) cell lines. However the two triple negative CMs induced a significant decrease in the cell lines' proliferation index, which was associated with a concomitant increase in cells' apoptotic index. Ultracentrifugation revealed that the apoptosis-inducing activity was retained in the pellet but not the supernatant of the CM. Negative staining electron microscopy (EM) revealed the presence of exosomes in the CM's ultra-centrifuged pellet, which stained positive for cd63 surface protein marker using an immunogold assay.
Conclusions: These data strongly suggest that some triple negative breast cancer cell lines posses exosome-mediated apoptosis-inducing activity. This activity may have biological and clinical relevance since it could be a factor participating in the selection of tumor cell subpopulations of different degrees of aggressiveness. Further proteomic and microRNA profiling of the exosomes is ongoing in order to characterize this exosome-mediated apoptosis-inducing activity.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-06-02.
Abstract P6-07-04: Evaluation of Adjuvant! Online for primary operable grade 2 breast cancers with 10-year follow-up
Authors: Van Calster B , Brouckaert O , Wildiers H , Christiaens M-R , Weltens C , Paridaens R , Van Limbergen E , Neven P ,   Multidisciplinary Breast Centre, UZ Leuven
Published: August 2014

Abstract
Background: In primary operable breast cancers, Adjuvant!Online (AOL) uses demographics and clinic-pathological markers to predict the 10-year breast cancer specific survival (BCSS) with and without adjuvant systemic therapy. Grade 2 BC is a difficult group for adjuvant treatment decisions. We compared the observed with the AOL-estimated BCSS rate in our centre in consecutive women primary operated for a grade 2 BC.
Patients and Methods: All patients with grade 2 primary operable breast cancer from UZL diagnosed between 1/1/2000 and 31/3/2002. After 10 years of follow-up, patients were evaluated for BCSS and dead from other cause. For each patient, the adjuvant! Online algorithm (version 8) was applied to predict BCSS taking the patients' adjuvant therapy into account. Adjuvant! Online was validated by assessing the calibration and discrimination. Discrimination was assessed by the area under the ROC curve. The expected BCSS rate was obtained by averaging the predicted probabilities of BCSS. Next, logistic calibration was performed by predicting observed BCSS within 10 years of follow-up with the odds of the predicted probability of BCSS (odds BCSS). In this analysis, the intercept should be 0 and the coefficient for odds BCSS 1 for perfect calibration of the predicted probabilities. A likelihood ratio test is used to test the null hypothesis of perfect calibration.

Results: Six patients were lost to follow-up. The median age at diagnosis of the remaining 445 patients was 56 years (IQR 48 to 67 years, range 26 to 89 years). In 433/445 cases (97%), the prediction from AOL was available. The median AOL predicted probability for BCSS was 89.1% (IQR 83.2 to 94.6%, range 20.3 to 98.9%). The observed BCSS rate was 93.3% whereas the AOL-expected rate was 86.7%. The likelihood ratio test for perfect calibration was statistically significant (p &lt; 0.0001), with an intercept of −1.55 (95% CI −2.33 to −0.84) and a coefficient for odds BCSS of 0.55 (95% CI 0.19 to 0.92). AOL strongly underestimated the probability of BCSS. The AUC was 0.65 (95% CI 0.53 to 0.76). For patients that did not die from BC within 10 years, the median estimated BCSS probability by AOL was 89.6% (IQR 83.5 to 94.6 %), whereas for patients that died from BC the median estimated probability was 83.9 % (IQR 77.9 to 94.5%).
Conclusion: Although Adjuvant! Online achieved moderate discrimination between those that did and those that did not die from BC within 10 years FU, it clearly underestimated the probability of BCSS in our sample.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-04.
Abstract P6-07-21: Signs and symptoms at central nervous system (CNS) relapse in breast cancer patients with Leptomeningeal carcinomatosis related with shorter survival after recurrence
Authors: Gomez HL , Schwarz LJ , Vásquez J , Neciosup SP , Pinto JA , Vidaurre T , Ferreyros G , Vallejos CS 
Published: August 2014

Abstract
Background: There are signs and symptoms detected at CNS relapse in breast cancer patients that could be identified as a poor prognosis feature of the disease.
Objectives: To describe the commonest signs and symptoms at CNS relapse and its relation with post SNC - recurrence survival in patients with leptomeningeal carcinomatosis (LMC).
Methods: We evaluated a retrospective cohort of 2597 women with breast cancer treated at the Instituto Nacional de Enfermedades Neoplásicas (Lima-Perú) in the period 2000–2005. Clinical data was retrieved from medical records. Breast cancer phenotypes were determined by IHC expression of hormonal receptors (HR) and HER2 and categorized in [HR+, HER2−], triple-negative (TN) [HR−, HER2−] and Her-2 [HR+/−, HER2 +]. The main endpoint was Post-CNS recurrence survival.
Results: A total of 157 cases had CNS relapse from which 124 had only brain metastases, 19 only leptomeningeal carcinomatosis (LMC), and 14 both. Forty three cases were [HR+, HER2−] (5 LMC), 68 were TN (13 LMC) and 51 were [HR+/−, HER2 +] (15 LMC). 152 cases were in clinical stages I-III at diagnosis (96.8% of all SNC relapses). There was no association between IHC phenotypes and age at CNS relapse, ECOG Performance Status (p = 0.837), extracraneal metastases (p = 0.304), control of primary tumor (p = 0.164), number or volume of brain metastases (p = 0.706). Significant association was found between phenotype and time from diagnosis to development of CNS metastases (≤8 months: 16.3% in TN, 7.3% in Her-2 and 0% for [HR+, HER2−]; p = 0.017) and histological grade (grade III: 74.4% in TN, 55.% in Her-2 and 30% for [HR+, HER2−]; p = 0.006). Symptoms/signs commonest in LMC patients were cephalea (7 cases, 72%), meningism (6, 24%), nausea (6, 24%), vomiting (5, 20%), ataxia (5, 20%), facial palsy (4, 16%), somnolence (4, 16%), paraparesia (3, 12%), hiporeflexia (3, 12%), apraxia (3, 12%), arreflexia (3, 12%), poor sphincter control (3, 12%), hemiparesia (2, 8%), seizures (2, 8%), bradypsichia (2, 8%), neuropathic pain (1, 4%). Meningism was most frequent in TN cases (50%). Post recurrence survival was shorter in LMC TN patients (3.61mo vs 4.89mo to [HR+, HER2−] vs 5.95mo to [HR+/−, HER2 +; p = 0.044] and in LMC patients with meningism (1.38mo vs 5.26mo; p = 0.02). Multivariate analysis identify meningism as the worse risk factor for survival in patients relapsed with LMC (HR: 4.33 compared with patients without LMC; p = 0.066).
Conclusions: In LMC patients, meningism was identified as a sign related to shorter survival after the SNC relapse.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-21.
Abstract P6-07-32: Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2 positive subtype is associated with the most favorable outcome
Authors: Tjan-Heijnen VCG , Lobbezoo DJA , van Kampen RJW , Voogd AC , Dercksen MW , van den Berkmortel F , Smilde TJ , van de Wouw AJ , Peters FPJ , van Riel JMGH , Peters NAJB , Borm GF 
Published: August 2014

Abstract
Background: In early breast cancer the different subtypes and their prognostic relevance are well known, contrary to the knowledge on prognostic relevance of subtypes in metastatic breast cancer. This study presents survival estimates after diagnosis of distant metastases of breast cancer subtypes in a recent cohort in which the treatment is representative of current clinical practice.
Patients and methods: All patients diagnosed with metastatic breast cancer in one of eight participating hospitals in the South-East part of the Netherlands between 2007–2009 were included and all medical charts were reviewed. Patients were categorized in 4 subtypes based on the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary tumor; HR positive/HER2 negative, HR positive/HER2 positive, HR negative/HER2 positive and triple negative (TN). Metastatic survival was estimated using the Kaplan-Meier product-limit method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders.
Results: A total of 815 patients were included; the HR+/HER2− subtype comprising 66%, the HR−/HER2+ subtype 8%, the TN subtype 15% and the HR+/HER2+ subtype 11% of patients. The four subtypes were associated with different metastatic survival times; the HR+/HER2+ subtype was associated with the best metastatic survival (median, 32.9 months), compared to 22.1 months for the HR+/HER2− subtype, 19.5 months for the HR−/HER2+ subtype and 7.7 months for the TN subtype. Aside from subtype, other prognostic factors of metastatic survival were site of metastases and metastatic-free interval.
Conclusion: Of the four subtypes, the HR+/HER2+ subtype was associated with the most favorable outcome, in terms of metastatic survival.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-32.