bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-06-02: Insulin receptor targeting in breast cancer through yeast surface display
Authors: Chan Jie Ying , Hackel Benjamin , Yee Douglas 
Published: May 2015

Abstract
Selective estrogen receptor modulators (SERMs) such as tamoxifen have been a conventional therapy for breast cancer patients expressing estrogen receptor, representing the most common breast cancer type. The development of secondary resistance to SERM is an unsolved clinical dilemma, leading to the exploration of more targeted therapies. The insulin-like growth factor (IGF) system is well documented and is implicated as a contributor to endocrine resistance. Unfortunately, antibodies directed against type I IGF receptor (IGF1R) failed to demonstrate efficacy in endocrine resistant breast cancer. We have previously shown that tamoxifen resistant (TamR) breast cancer cells lose IGF1R yet retain expression of insulin receptor (InsR), a closely related receptor to IGF1R. Thus, we hypothesized that InsR may serve as a compensatory pathway to the loss of IGF1R in TamR cells and InsR may be a target in the therapy of endocrine resistant breast cancer. Indeed, our preliminary results show that TamR breast cancer cells were more sensitive to insulin stimulation. As compared to the parental cells, TamR cells showed stronger PI3K/AKT and MAPK/ERK activation, greater MTT proliferation growth and anchorage-independent growth upon insulin treatment. Knocking down InsR in TamR cells with shRNA was able to attenuate their sensitivity towards insulin-mediated PI3K/MAPK activation and growth, suggesting InsR targeting may be necessary in endocrine resistant breast cancer. To develop new agents to target InsR, we used yeast surface display to develop an InsR-selective protein scaffold – the 10th type III domain of human fibronectin (Fn3). This technique has arisen as an alternative method for the development of specific binders of cell surface proteins. Compared to antibodies, the Fn3 proteins are smaller (∼10kDa), thermally more stable, lack disulfide bonds and have the ability to bind a large variety of proteins. Using error-prone polymerase mutagenesis, we identified improved Fn3 proteins with increased InsR affinity, specificity, and stability. Our current results show that InsR is an important target in endocrine resistant breast cancer cells. Development of engineered Fn3 peptides with increased InsR binding specificity and affinity for InsR compared to IGF1R could be used to disrupt signaling through this pathway. Engineered Fn3 will further be evaluated as a potential imaging and therapeutic tool.
Citation Format: Jie Ying Chan, Benjamin Hackel, Douglas Yee. Insulin receptor targeting in breast cancer through yeast surface display [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-06-02.
Abstract P4-06-04: Targeting the PI3K-AKT-mTOR and RAF-MEK-ERK pathways in HER2 amplified breast cancer models
Authors: De Pradip , Sun Yuliang , Carlson Jennifer , Friedman Lori , Dey Nandini , Leyland-Jones Brian 
Published: May 2015

Abstract
Background: The PI3K-AKT-mTOR and the RAF-MEK-ERK signaling pathways are critical for normal physiology and also commonly dysregulated in several cancers including breast cancer. Inhibition of one pathway can still result in the maintenance of signaling and tumor progression via the other reciprocal pathway. Here, we hypothesize that due to the existence of such "escape" mechanisms a dual targeting of these pathways may lead to superior therapeutic activity in HER2+ breast tumors. Methodology: This study evaluated the combination of a pan-PI3K inhibitor GDC-0941 and a MEK1/2 inhibitor GDC-0973 in different HER2+ breast cancer cell lines. HER2+/trastuzumab (T)-sensitive (BT474), HER2+/trastuzumab-resistant (BT474HerR) and HER2+/PIK3CA mutated (HCC1954) cells were used for this study. Growth inhibition/survival, apoptosis, signal transduction and antitumor efficacy were examined using 3D-ON-TOP assays, annexinV staining and mouse xenografts respectively, in T-sensitive, T-resistant and HER2+/PIK3CA mutated breast cancer cell lines. Results: 1) treatment with GDC-0941 caused dose dependent inhibition of phosphorylation of AKT (S473, T308), P70S6K, S6RP, and 4EBP1 (T37/46) and the combination of GDC-0941 plus GDC-0973 more effectively blocked p-S6RP and p-4EBP1, especially in BT474HerR and HCC1954 cells, 2) GDC-0973 inhibited activation of ERK and this inhibition was sustained when combined with GDC-0941, 3) all cell lines showed an increase in annexin V positivity (index of apoptosis) following the treatment of GDC-0941 alone and a combination of GDC-0941 plus GDC-0973 more effectively induced apoptosis in HER2+ cell lines, 4) similar to anti-proliferative and pro-apoptotic signals, a combination of GDC-0941 plus GDC-0973 more effectively abrogated anchorage-independent colony formation in 3D-ON-TOP assay and 5) xenograft data exhibited that the combination of T plus GDC-0941 has an enhanced anti-tumor effect in T-sensitive (80%), T-resistant (82%) and PIK3CA mutated models (58%), and most importantly, tumor regression was more pronounced in all three models when mice were treated with T plus GDC-0941 plus GDC-0973. Conclusions: Our findings suggest that simultaneous administration of MEK1/2 inhibitor may enhance the antitumor activity of PI3K targeted drug and may delay the appearance of resistance of HER2-targeted therapy in HER2 amplified breast cancer.
Citation Format: Pradip De, Yuliang Sun, Jennifer Carlson, Lori Friedman, Nandini Dey, Brian Leyland-Jones. Targeting the PI3K-AKT-mTOR and RAF-MEK-ERK pathways in HER2 amplified breast cancer models [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-06-04.
Abstract P4-06-06: Growth hormone induction of oncogenic signaling promotes survival of endocrine resistant breast cancer cells
Authors: Beckwith Heather C , Yee Douglas 
Published: May 2015

Abstract
Targeting endocrine resistant breast cancer cells has been successfully accomplished by the use of mTORC1 inhibitors in combination with either aromatase inhibitors or tamoxifen. While there was preclinical data suggesting that targeting of the type I IGF receptor (IGF1R) might also be a target for endocrine resistant cells, clinical trials using IGF1R monoclonal antibodies showed no advantage and even suggested potential harm for the combination. IGF1R inhibition results in the disruption of an endocrine feedback loop and results in elevation of the pituitary growth factor growth hormone (GH). GH is involved in normal human growth, development, metabolism, and longevity. Growth hormone released from the pituitary stimulates production of IGF-I from the liver. The GH/IGF-1 axis is known to promote mammary gland hyperplasia and breast cancer carcinogenesis. Previous studies have shown that GH promotes carcinogenesis independently of insulin-like growth factor. The role of GH in specific subtypes of breast carcinoma remains to be defined. Our laboratory has found that estrogen receptor positive breast cancer cell lines up regulated oncogenic STAT5, Akt, and MAPK signaling pathways in response to GH. Tamoxifen resistant (TamR) and long-term estrogen deprived (LTED) breast cancer cell lines derived from MCF-7 and T47D cells demonstrated increased oncogenic signaling in response to GH compared to the corresponding parental cell lines from which they were derived. In contrast, GH stimulation of a triple negative breast cancer cell line (MDA-MB-231) failed to induce signaling via these oncogenic pathways. Although GH treatment of parental, TamR, and LTED breast cancer cells had minimal effect on cell proliferation, cell cycle progression, or migration; GH signaling protected cells from cytotoxic chemotherapy induced apoptosis. This data shows that GH signaling is found in endocrine sensitive and resistant cells. Furthermore, GH may function in protecting cells from cell death induced by either endocrine or cytotoxic drugs. GH receptor blockade may be a valid treatment option for endocrine resistant breast cancer.
Citation Format: Heather C Beckwith, Douglas Yee. Growth hormone induction of oncogenic signaling promotes survival of endocrine resistant breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-06-06.
Abstract P4-06-07: Expression of growth hormone releasing hormone receptor ( GHRH-R ) in primary and metastatic mammary carcinomas
Authors: Nadji Mehrad , Block Norman L , Shally Andrew V , Lara Jonathan , Michaelson Rick , Ali Suhail M , Leitzel Kim , Rizvi Syed M , Al-Marrawi Mhd Yaser , Lipton Allan 
Published: May 2015

Abstract
In addition to its nominative function as a neurohormone acting on the pituitary, Growth Hormone Releasing Hormone (GHRH) has been shown to modify the growth behavior of numerous cancers, including breast. GHRH is produced by tumor cells, acts in an autocrine/paracrine manner, and requires the presence of GHRH receptor (GHRH-R) on the tumor cells to exert its effects. As this work has been done predominantly on tumor cell lines and xenografts, we set out to examine the clinical analog.
Matched primary and metachronous metastases from 50 breast cancers were included in this study of GHRH-R in breast cancer. Immunohistochemistry for GHRH-R (AbCam) was performed on paraffin sections and the staining results were assessed semi quantitatively from 0 (negative) to 3+ (strongly positive). A section from normal pituitary was used as positive control. Forty-three of the primary breast cancers (86%) that ultimately relapsed or metastasized showed moderate to strong immunohistochemical expression of GHRH-R. Tumors from the metastatic foci also showed strong immunoreactivity in 78%, 71%, and 44% of liver, brain, and bone foci, respectively. The lower intensity of staining in bone samples may be due to the effect of the decalcification process routinely performed before staining. Whenever present, the non-neoplastic glands adjacent to breast tumors showed either negative or 1+ reaction for GHRH-R. We conclude that the great majority of mammary carcinomas at primary and metastatic sites express GHRH-R. This finding could potentially serve as a basis for therapeutic approaches using peptide receptor antagonists. By receptor blockade using GHRH receptor antagonists, with minimal pharmacologic side-effects, we have been able to control the growth in a number of tumor cell lines (HCC1806, MDAMB468, MDAMB435S, MCF7, T47D, HCC1937, BT474, and MX1s). Based on the presence of GHRH receptors in these clinical tumors, we conclude that clinical trials evaluating GHRH receptor antagonists are indicated.
Citation Format: Mehrad Nadji, Norman L Block, Andrew V Shally, Jonathan Lara, Rick Michaelson, Suhail M Ali, Kim Leitzel, Syed M Rizvi, Mhd Yaser Al-Marrawi, Allan Lipton. Expression of growth hormone releasing hormone receptor ( GHRH-R ) in primary and metastatic mammary carcinomas [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-06-07.
Abstract P4-07-04: Immunohistochemical determination of arylamine N-acetyltransferase 1 (NAT1) as the target of miR-1290 and prognostic biomarker of breast cancer
Authors: Endo Yumi , Yamashita Hiroko , Takahashi Satoru , Sato Shinya , Yoshimoto Nobuyasu , Asano Tomoko , Hato Yukari , Yamaguchi Mina , Dong Yu , Toyama Tatsuya 
Published: May 2015

Abstract
Introduction: There are large-scale molecular differences between estrogen receptor α (ERα)-positive breast cancer and ER-negative breast cancers. In ERα-positive breast cancer, recent analyses have shown that ERα-positives can be divided into two subtypes such as luminal A and luminal B. These subtypes differ in characteristics such as response to endocrine therapy and chemotherapy, and prognosis. In a previous study, we identified a microRNA, miR-1290, that was significantly down-regulated in luminal A tumors and its potential target arylamine N-acetyltransferase 1 (NAT1). The aim of this study was to clarify whether NAT1 is a bona fide target of miR-1290, and to investigate the impact of NAT1 on breast cancer prognosis. Methods: Luciferase reporter assay was employed to validate NAT1 as a putative miR-1290 target gene. Protein expressions of NAT1, ERα, progesterone receptor (PgR) and HER2 were analyzed in 394 breast cancer samples by immunohistochemistry. Results: NAT1 was shown to be a direct target of miR-1290 by luciferase reporter assay. Expression levels of NAT1 were positively correlated with expression levels of ERα (P &lt; 0.0001) and PgR (P &lt; 0.0001), whereas expression levels of NAT1 were negatively correlated with both tumor grade and tumor size (P &lt; 0.0001). Kaplan-Meier analysis showed that NAT1 presence was significantly associated with increased overall survival (OS) (P = 0.0416) in breast cancer patients (n=394). Similarly, significant associations of NAT1 presence were shown with disease-free survival (DFS) (P = 0.0048) and OS (P = 0.0055) in patients who received adjuvant endocrine therapy with tamoxifen (n = 176). Moreover, NAT1 presence was also significantly associated with increased DFS (P = 0.0025) and OS (P = 0.0007) in lymph node-positive breast cancer patients (n=147). Univariate and multivariate analyses showed significant associations between expression levels of NAT1 and DFS (P = 0.0005 and 0.019, respectively). Conclusion: We reported that miR-1290 directly targets NAT1 3’-UTR and NAT1 protein expression is correlated with improved OS of breast cancer. Moreover, NAT1 is a possible prognostic biomarker for lymph node-positive breast cancer. Thus, miR-1290 and its potential target NAT1 are associated with characteristics of breast cancer.
Citation Format: Yumi Endo, Hiroko Yamashita, Satoru Takahashi, Shinya Sato, Nobuyasu Yoshimoto, Tomoko Asano, Yukari Hato, Mina Yamaguchi, Yu Dong, Tatsuya Toyama. Immunohistochemical determination of arylamine N-acetyltransferase 1 (NAT1) as the target of miR-1290 and prognostic biomarker of breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-07-04.
Abstract P4-11-25: Reappraisal of conventional risk stratification for local recurrence based on clinical outcomes in 285 resected phyllodes tumors of the breast
Authors: Yom Cha Kyong , Han Wonshik , Kim Sung-Won , Park So Yeon , Park In-Ae , Noh Dong-Young 
Published: May 2015

Abstract
Background A second resection has been recommended, to ensure a surgical margin of ≥ 1cm for the effective treatment of PTB, but the outcomes of an extensive series of cases casts this clinical approach in doubt.
Objective To identify the local recurrence risk factors of phyllodes tumor of the breast (PTB) and determine future optimal surgical treatment according to verified risks.
Methods All cases given a diagnosis of PTB and resected between 1989 and 2008 were retrospectively evaluated. Clinicopathologic data and clinical outcomes were analyzed and stratified according to the risks for local recurrence (LR).
Results All 285 cases occurred and 200 (70.2%) categorized as benign, 51 (17.9%) as borderline, and 34 (11.9) as malignant. Median follow-up was 6.7 years and during follow-up, there were 20 LRs. All benign PTBs recurred as benign PTB lesions. Mitosis (p = 0.007) and tumor size (p = 0.029) were independent prognostic factors for LR in multivariate analysis. Neither margin status (p = 0.773) nor type of surgery (p = 0.922) had any significance for LR.
[table 1] Local relapse-free survival by Cox-regressionSubgroup of patientsNo recurrence(%)Recurrence(%)UnivariateMultivariateHRpHRpMitosis0.0250.0071∼4/10HPF170(96.0)7(4.0)5∼9/10HPF33(84.6)6(15.4)4.2590.0094.2970.014≥10/10HPF15(88.2)2(11.8)3.4610.12212.2110.007Size0.0350.029≤2cm75(98.7)1(1.3)2cm&lt; and ≤5cm136(89.5)16(10.5)8.5990.0375.6300.010&gt;5cm51(98.1)1(1.9)1.5640.7520.3600.519Operation0.9570.922WLE229(93.1)17(6.9)VABS23(92.0)2(8.0)1.2470.7691.3960.814Mastectomy13(92.9)1(7.1)1.0550.9591.4720.744Margin0.8460.773Clear200(93.5)14(6.5)Close/Involvement39(92.9)3(7.1)1.1321.253
In the risk stratification for LR, PTBs sized 2 - 5cm with ≥ 10 mitoses / 10 HPF had the highest LR rate (60%) compared with all other groups (p &lt; 0.001).
Conclusions Only PTB with 2 - 5 cm and frequent mitoses, is it recommended to follow to ascertain a wide excision and clear margin of 1 cm, it necessary by means of a 2nd surgery could be considered to avoid the risk of LR in this distinct group.
Citation Format: Cha Kyong Yom, Wonshik Han, Sung-Won Kim, So Yeon Park, In-Ae Park, Dong-Young Noh. Reappraisal of conventional risk stratification for local recurrence based on clinical outcomes in 285 resected phyllodes tumors of the breast [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-25.
Abstract P4-11-27: Prospective comparison of conventional clinicopathological factors, uPA/PAI-1 and EndoPredict®-clin score (EPclin) for adjuvant clinical decision making in ER-positive, HER2-negative breast cancer: Progesterone receptor expression is strongly associat
Authors: Ettl Johannes , Große Lackmann Kirsten , Hapfelmeier Alexander , Klein Evelyn , Paepke Stefan , Petry Christoph , Specht Katja , Wolff Laura , Höfler Heinz , Kiechle Marion 
Published: May 2015

Abstract
Background: Recently, EPclin, a second generation multigene test has been introduced into clinical practice. Aim of this prospective study is to compare conventional clinicopathological factors, uPA/PAI-1 and EPclin and to determine, how these parameters influence adjuvant treatment decisions. Methods: 217 consecutive cases of ER-pos, HER2neg, breast cancer cases were enrolled in this study. Conventional clinicopathological factors, uPA/PAI-1 and EPclin were obtained by central pathology assessment of the patients' surgical specimen. Decision for type of adjuvant treatment was made twice – once with and once without EPclin result- after case discussion in an interdisciplinary tumor conference. Results: 217 Patients (pt) have been evaluated. Tumor grading within the presented cohort was as follows: G1: 44 pt (20%), G2: 146 pt (68%), G3: 27 pt (12%). 59 pt (27%) had positive axillary lymph node involvement. 57 pt (26%) were pT1a/b. EPclin could be assessed in all patients. 85 pt (39%) were classified as "high risk" whereas 132 pt (61%) were classified as "low risk". uPA/PAI was obtained from 123 pt (57%). 64 pt (52%) out of these had high uPA/PAI-1 levels whereas 59 pt (48%) showed low uPA/PAI-1 levels. Level of progesterone receptor (PR) expression was obtained from 216 pt. 39 pt (18%) had low or absent PR expression (PR ≤ 20%). 26 pt (67%) of this low PR expression group were classified as EPclin high risk. Furthermore 118 pt (67%) of the high PR expression group (177 pt) were classified as "low risk" via EPclin (p&lt;0,0001). In 89 cases (41%) treatment decision was influenced by EPclin: In 73pt (34%) adjuvant chemotherapy (ctx) was omitted whereas in 16 pt (7%) ctx was added following the EPclin result. Conclusions: This prospective study shows for the first time, that PR expression is strongly associated with risk score evaluated by EPclin testing. In comparison with uPA/PAI-1 and conventional clinicopathological factors EPclin is the more powerful tool to help reduce unnecessary adjuvant chemotherapy.
Citation Format: Johannes Ettl, Kirsten Große Lackmann, Alexander Hapfelmeier, Evelyn Klein, Stefan Paepke, Christoph Petry, Katja Specht, Laura Wolff, Heinz Höfler, Marion Kiechle. Prospective comparison of conventional clinicopathological factors, uPA/PAI-1 and EndoPredict®-clin score (EPclin) for adjuvant clinical decision making in ER-positive, HER2-negative breast cancer: Progesterone receptor expression is strongly associat [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-27.
Abstract P4-11-36: Prognostic models in male breast cancer
Authors: vanderPol Carmen C , Lacle Miangela M , Witkamp Arjen J , Kornegoor Robert , Hui Miao , Bouchardy Christine , vanderWall Elsken , Verkooijen Helena M , vanDiest Paul J 
Published: May 2015

Abstract
Male breast cancer (MBC) is a rare disease and its treatment is largely extrapolated from its female counterpart.
Accurate prognostication is essential for advising on adjuvant systemic treatment and informing patients. Several predictive models are available for female breast cancer (FBC) including, subsequently, the Morphometric Prognostic Index (MPI), Nottingham Prognostic Index (NPI), Adjuvant! and Predict. The aim of this study was therefore to compare the prognostic performance of these models in a group of 166 early MBC patients.
The MPI describes a "good"- (MPI&lt;0,60) and a "poor" prognostic group (MPI&gt;=0,60) by using a formula with mitotic activity index, tumour size and lymph node status. The NPI is calculated by a formula including size, number of lymph nodes with metastases and tumour grade and divides patients into three groups; "good-" (NPI &lt;= 3,4), "intermediate-" (3,4&lt;NPI&gt;=5,4) and "poor" prognosis (NPI&gt;5,4). For the programs Adjuvant!Online and Predict, similar groups with "good"-, "intermediate"- and "poor" prognosis were defined by using tertiles. The prognostic performance of each test was studied by using the logrank-test and comparison between the models was done by using C-statistics.
The mean age was 66,4 years old and the median survival was 4,6 years with a mean of 5,8 years overall survival.
Survival of the highest predicted group was higher (MPI: 87%, NPI: 90%, Adjuvant!Online: 91% and Predict: 88%) than for the moderate groups (NPI: 76%, Adjuvant!Online: 77% and Predict: 75%) and lowest for the poor predicted groups (MPI: 51%, NPI: 43%, Adjuvant!Online: 45% and Predict: 42%), with p-values that were highly statistically significant.
In terms of discrimination, all models were moderately able to discriminate between good and poor survivors (C-statistics; MPI; 0,674, NPI; 0,678, Adjuvant!Online; 0,717 and Predict; 0,711).
In conclusion, the MPI, NPI, Adjuvant! and Predict, prognostic models that were originally developed and validated for FBC, perform fairly well for MBC. These models may therefore help in MBC prognostication and decisions on adjuvant systemic therapy.
Citation Format: Carmen C vanderPol, Miangela M Lacle, Arjen J Witkamp, Robert Kornegoor, Miao Hui, Christine Bouchardy, Elsken vanderWall, Helena M Verkooijen, Paul J vanDiest. Prognostic models in male breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-36.