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  • 1
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2010-12)
    Abstract: Over-expression of HER2 in a subset of breast cancers ( HER2 +) is associated with high histological grade and aggressive clinical course. Despite these distinctive features, the differences in response of HER2 + patients to both adjuvant cytotoxic chemotherapy and targeted therapy (e.g. trastuzumab) suggests that unrecognized biologic and clinical diversity is confounding treatment strategies. Furthermore, the small but established risk of cardiac morbidity with trastuzumab therapy compels efforts towards the identification of biomarkers that might help stratify patients. Methods A single institution tissue array cohort assembled at the Clearview Cancer Institute of Huntsville (CCIH) was screened by immunohistochemistry staining using a large number of novel and commercially available antibodies to identify those with a univariate association with clinical outcome in HER2 + patients. Staining with antibody directed at TRMT2A was found to be strongly associated with outcome in HER2 + patients. This association with outcome was tested in two independent validation cohorts; an existing staining dataset derived from tissue assembled at the Cleveland Clinic Foundation (CCF), and in a new retrospective study performed by staining archived paraffin blocks available at the Roswell Park Cancer Institute (RPCI). Results TRMT2A staining showed a strong correlation with likelihood of recurrence at five years in 67 HER2 + patients from the CCIH discovery cohort (HR 7.0; 95% CI 2.4 to 20.1, p 〈 0.0004). This association with outcome was confirmed using 75 HER2 + patients from the CCF cohort (HR 3.6; 95% CI 1.3 to 10.2, p 〈 0.02) and 64 patients from the RPCI cohort (HR 3.4; 95% CI 1.3-8.9, p 〈 0.02). In bivariable analysis the association with outcome was independent of grade, tumor size, nodal status and the administration of conventional adjuvant chemotherapy in the CCIH and RPCI cohorts. Conclusions Studies from three independent single institution cohorts support TRMT2A protein expression as a biomarker of increased risk of recurrence in HER2+ breast cancer patients. These results suggest that TRMT2A expression should be further studied in the clinical trial setting to explore its predictive power for response to adjuvant cytotoxic chemotherapy in combination with HER2 targeted therapy.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 2041352-X
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  • 2
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2010
    In:  Pediatric Radiology Vol. 40, No. 5 ( 2010-5), p. 773-776
    In: Pediatric Radiology, Springer Science and Business Media LLC, Vol. 40, No. 5 ( 2010-5), p. 773-776
    Type of Medium: Online Resource
    ISSN: 0301-0449 , 1432-1998
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 1463007-2
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  • 3
    In: International Journal of Cancer, Wiley, Vol. 134, No. 6 ( 2014-03-15), p. 1422-1435
    Abstract: What's new? Differences exist between African‐American and European‐American women when it comes to breast cancer. But while these differences may be explained in part by nutritional factors, such as intake of folate and other methyl‐group nutrients, few studies have explored this possibility. Here, an inverse association was found between natural food folate intake and breast cancer risk in premenopausal and estrogen receptor (ER)‐positive African Americans. By comparison, a positive association was found for synthetic folate intake in European Americans. Thus, race, menopausal and ER status, and folate source may influence a possible link between folate intake and breast cancer risk.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 4
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 32, No. 1_Supplement ( 2023-01-01), p. IA011-IA011
    Abstract: Background Aberrant activation of the mammalian Target of Rapamycin (mTOR) pathway has been linked to obesity and endocrine therapy resistance, factors that may contribute to Black White disparities in breast cancer outcomes. We evaluated associations of race and clinicopathological characteristics with mRNA expression of key mTOR pathway genes in breast tumors. Methods Surgical tumor tissue blocks were collected from 367 newly diagnosed breast cancer patients (190 Black and 177 White). Gene expression of AKT1, EIF4EBP1, MTOR, RPS6KB2, and TSC1 were quantified by NanoString nCounter. Differential gene expression was assessed using linear regression on log2-transformed values. Gene expression and DNA methylation data from TCGA were used for validation and investigation of race-related differences. Results Compared to White women, Black women had relative under-expression of AKT1 (log2 fold-change = - 0.31, 95% CI - 0.44, - 0.18) and RPS6KB2 (log2 fold-change = - 0.11, 95% CI - 0.19, - 0.03). Higher vs. lower tumor grade was associated with relative over-expression of EIF4EBP1 and RPS6KB2, but with lower expression of TSC1. Compared to luminal tumors, triple-negative tumors had relative under-expression of TSC1 (log2 fold-change = - 0.42, 95% CI - 0.22, - 0.01). The results were similar in the TCGA breast cancer dataset. Post-hoc analyses identified differential CpG methylation within the AKT1 and RPS6KB2 locus between Black and White women. Conclusions Over-expression of RPS6KB2 and EIF4EBP1 and under-expression of TSC1 might be indicators of more aggressive breast cancer phenotypes. Differential expression of AKT1 and RPS6KB2 by race warrants further investigation to elucidate their roles in racial disparities of treatment resistance and outcomes between Black and White women with breast cancer. Citation Format: Mmadili N. Ilozumba, Song Yao, Adana A. M. Llanos, Angela R. Omilian, Weizhou Zhang, Susmita Datta, Chi Chen Hong, Warren Davis, Thaer Khoury, Elisa V. Bandera, Michael Higgins, Christine B. Ambrosone, Ting Yuan David Cheng. mTOR pathway gene expression in association with race and clinicopathological characteristics in Black and White breast cancer patients [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA011.
    Type of Medium: Online Resource
    ISSN: 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 1153420-5
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 869-869
    Abstract: Background: Aberrant activation of the mammalian Target of Rapamycin (mTOR) pathway is implicated in breast carcinogenesis and outcomes. Based on protein expression data, the activation could be heterogeneous by race, body fatness, and tumor clinicopathological characteristics. To understand potential impacts of mTOR pathway signaling in breast cancer, we evaluated the association of race and clinicopathological characteristics with gene expression of select mTOR pathway genes in breast tumors. Methods: Study participants were from the Women's Circle of Health Study (WCHS), complemented with samples from the Roswell Park Pathology Network Shared Resource (PNSR). Tumor tissue blocks were collected from 367 newly-diagnosed breast cancer cases (190 Black and 177 White women). Gene expressions of AKT1, EIF4EBP1, MTOR, RPS6KB2, TSC1 were quantitated using NanoString assays. Generalized linear models were performed to relate gene expression levels with demographic and clinicopathological variables. The regression coefficient (β) was converted to percentage difference. Additionally, we conducted an external validation of mTOR gene expression using data from The Cancer Genome Atlas (TCGA; N=332). Results: Study participants were mostly within the ages of 51 to 65 years old. Black women had lower expression levels of AKT1, MTOR, RPS6KB2 and TSC1 compared to White women. Black race vs White race was significantly associated with lower gene expression of AKT1 (-21.34%, 95% CI = -31.61%, -8.61%) and RPS6KB2 (-12.19%, 95% CI = -19.75%, -3.92%). The racial differences in expression levels of these two genes were consistent across luminal A, luminal B, HER2-enriched, and triple-negative subtypes. Higher tumor grade was associated with higher expression levels of EIF4EBP1 and RPS6KB2, but with lower expression of TSC1. In comparison to luminal A tumors, luminal B tumors had higher expression of RPS6KB2 (17.35%, 95% CI = 4.08%, 32.31%); whereas HER2-enriched (-23.66%, 95% CI= -41.73%, -1.00%) and triple-negative (-22.89%, 95% CI= -40.55%, -1.00%) had lower expression of TSC1. All these associations were unchanged after additionally adjusting for body mass index in a subset. Similarly, results from the TCGA data showed that in comparison to luminal A tumors, luminal B tumors had higher expression of RPS6KB2 (53.73%, 95% CI = 27.12%, 87.76%) whereas HER2-enriched had a lower expression of TSC1 (-26.66%, 95% CI = -43.45%, -4.88%) and triple-negative subtype had a lower expression of TSC1 (-17.30%, 95% CI = -50.68%, -3.05%). Conclusions: Variables such as race and breast cancer subtypes should be considered in studying the mTOR pathway genes in breast cancer tumors. Citation Format: Mmadili N. Ilozumba, Song Yao, Adana A. Llanos, Angela Omilian, Weizhou Zhang, Susmita Datta, Chi-Chen Hong, Warren Davis, Thaer Khoury, Christine B. Ambrosone, Ting-Yuan D. Cheng. Breast tumor gene expression in the mTOR pathway and clinicopathological characteristics in Black women and White women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 869.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. P4-06-04-P4-06-04
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P4-06-04-P4-06-04
    Abstract: BACKGROUND: The residual cancer burden (RCB) is calculated utilizing these variables: tumor bed size, tumor/tumor bed ratio, percentage of DCIS, number of positive lymph nodes (LN) and the size of the largest LN. The aim of the study is to investigate if other variables related to the LNs correlate with the outcomes. METHODS: We conducted pathologic review of 129 patients who had triple negative breast cancer (TNBC) diagnosed between 2002 and 2006. The following variables were calculated, Finv: primary tumor/tumor bed ratio; dmet: diameter of largest involved LN; dprim= √d1d2 (d1 and d2 dimensions of the primary tumor bed); RCBprim = finv dprim ; RCBmet = 4 (1- 0.75LN) dmet; and RCB = 1.4 (finvdprim)0.17 + [4(1- 0.75 LN) dmet ]0.17. We calculated the LN tumor/tumor bed ratio (fLN), the number of resected LNs, and the number of LNs with therapy effect (with or without metastases). Clinical staging was abstracted from the medical records. Clinicopathologic variables were correlated with the recurrence free survival (RFS) and overall survival (OS). RESULTS: Most of the patients were treated with anthracycline based chemotherapy (CT) (90.7%). The median and range of follow up was 108.2 (15.0, 225.1) months. Pathology complete response (pCR) was achieved in 34.1% of the patients and correlated with age (p= 0.042) and clinical stage (p=0.004). pCR had better survival after 5-years (p & lt;0.001) and 10 years (p=0.001) follow up. In the univariate analysis the following variables were statistically significant correlating with RFS and OS including clinical stage, RCB, and fLN. These variables were statistically significant in the multivariate analysis for RFS including clinical stage with hazard ratio (HR) 0.37 (0.15, 0.89) (p=0.026) and fLN HR 1.01 (1.00, 1.02) (p=0.006); and for OS with HR 0.35 (0.14, 0.85) (p=0.02) and 1.01 (1.00, 1.02) (p=0.01), respectively. CONCLUSIONS: Adding LN tumor/tumor bed ratio (fLN) to the existing formula may improve the predictability power of the RCB index. Citation Format: Shipra Gandhi, Kristopher Attwood, Wenyan Ji, Saif Aljabab, Thaer Khoury. The role of axillary lymph node status in residual cancer burden calculation of triple negative breast cancer post-neoadjuvant cytotoxic chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-06-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
    In: Molecular Nutrition & Food Research, Wiley, Vol. 66, No. 12 ( 2022-06)
    Abstract: Dietary isothiocyanates (ITCs) from cruciferous vegetables have shown potent anti‐breast cancer activities in preclinical models, but their anticancer effects in vivo in breast cancer patients remain elusive. A proof‐of‐principle, presurgical window of opportunity trial is conducted to assess the anticancer effects of dietary ITCs in breast cancer patients. Methods and Results Thirty postmenopausal breast cancer patients are randomly assigned to receive ITC‐rich broccoli sprout extract (BSE) (200 µmol ITC per day) or a placebo for 2 weeks. Expression of biomarkers related to ITCs functions are measured in breast cancer tissue specimens at pre‐ and post‐interventions using immunohistochemistry staining. First morning urine samples are collected at both timepoints for proteomic analysis. Overall, the study shows high compliance (100%) and low toxicity (no grade 4 adverse event). Trends of increase in cleaved caspase 3 and tumor‐infiltrating lymphocytes (TILs) and trends of decrease in Ki‐67 and nuclear to cytoplasm ratio of estrogen receptor (ER)‐α are observed in the BSE arm only, consistent with the significantly altered signaling pathways identified in urinary proteomic analysis. Conclusions Anticancer activities of ITCs are observed in breast cancer patients, supporting the potential beneficial roles of ITC‐containing cruciferous vegetables in breast cancer prognosis.
    Type of Medium: Online Resource
    ISSN: 1613-4125 , 1613-4133
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2160372-8
    SSG: 12
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3242-3242
    Abstract: Background: Women of African ancestry (AA) have higher breast cancer mortality than other US racial/ethnic groups, attributed to a number of social and economic factors. However, breast tumors in AA women are more likely to present with higher grade and lacking estrogen receptor (ER) expression compared to those from women of European ancestry (EA), suggesting the importance of tumor factors in breast cancer disparities. Emerging evidence suggests that stromal tumor-infiltrating lymphocytes (TIL-str) have a role in immune response to therapy and prognosis of breast cancer. The objective of this study was to examine associations between risk factors for breast cancer and TIL-str, with consideration of tumor characteristics. Methods: We reviewed the hematoxylin and eosin slides from surgical or biopsy tumor blocks of invasive breast cancer from 1,385 cases (986 AA and 399 EA women, aged 20-75 years) in the Women's Circle of Health Study, a multicenter case-control study in New York and New Jersey. In-person interviews were conducted at diagnosis to obtain data on demographics, family histories, hormone use, and reproductive and menstrual histories. Anthropometric measurements were taken by trained staff. TIL-str were scored as 0%, 1%, and 10% to 100% in increments of 10%. Linear regressions were performed to estimate differences in TIL-str scores (β). Results: In univariate analysis, TIL-str was higher in tumors from AA than those from EA women overall (mean score = 21.5% vs. 12.5; P & lt;0.001). TIL-str score was positively associated with higher grade, larger tumor size, and ER and progesterone receptor (PR) negativity in both AA and EA women (all P & lt;0.05). In EA women, TIL-str score was also higher in more advanced than early stage tumors and human epidermal factor receptor 2 (HER2) positive than negative tumors (both P & lt;0.05), but not in AA women. In multivariable analysis, AA compared to EA race was significantly associated with a higher TIL-str score (β = 5.7%, P & lt;0.001), adjusting for age at diagnosis, body mass index, menopausal status, tumor grade, size, stage, and molecular subtypes defined by ER, PR, and HER2. There was no apparent association between TIL-str and history of breast cancer in first-degree relatives, history of benign breast disease, hormone use, reproductive factors, or body size. Conclusion: Self-reported African compared to European ancestry is independently associated with higher TIL-str scores in breast tumors. Our findings suggest that immune response may play a role in the differences in breast cancer biology and outcomes between AA and EA women. (Funding: The Breast Cancer Research Foundation; NIH P01CA151135, R01CA100598, R01CA185623, P30CA072720, K07CA201334; US Army Medical Research and Material Command DAMD-17-01-1-0334) Citation Format: Ting-Yuan D. Cheng, Rochelle Payne Ondracek, Song Yao, Warren Davis, Angela Omilian, Mateusz Opyrchal, Elisa V. Bandera, Michael J. Higgins, Christine B. Ambrosone, Thaer Khoury. Differences in stromal tumor-infiltrating lymphocytes in breast cancer from women of African and European ancestry after accounting for tumor characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3242.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 23, No. 6 ( 2014-06-01), p. 1115-1120
    Abstract: The effects of reproductive factors on breast cancer risk seem to differ by estrogen receptor (ER) status. Menarche and first live birth (FLB) tend to occur at younger ages in African Americans (AA) than European Americans (EA), and could play a role in breast cancer disparities. In the Women's Circle of Health Study, a case–control study of breast cancer in EA and AA women, in-person interviews were conducted to collect epidemiologic data, including reproductive histories. Data on ER status, abstracted from pathology reports, were available for 814 AA and 538 EA breast cancer cases, and were analyzed with 1015 AA and 715 EA controls, to evaluate associations between subgroups and age at menarche, age at FLB, and the interval between those ages. Among AA women, later age at menarche (≥14 years) was associated with reduced risk of both ER+ and ER− breast cancer, with ORs strongest for ER− disease [OR = 0.57; 95% confidence interval (CI), 0.37–0.88]; associations were weaker and nonsignificant for EA women. There were no significant associations with age at FLB, but AA women with a FLB within 15 years of menarche had increased risk of ER− disease (OR = 2.26; 95% CI, 1.29–3.95), with no significant associations among EAs. In our data, earlier age at menarche and shorter intervals until FLB are associated with ER− breast cancer in AA women; differential distributions by race of these and other reproductive risk factors could contribute to the higher prevalence of ER− breast cancer in AA women. Cancer Epidemiol Biomarkers Prev; 23(6); 1115–20. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 10
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Research Vol. 16, No. 8_Supplement ( 2018-08-01), p. A60-A60
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 8_Supplement ( 2018-08-01), p. A60-A60
    Abstract: Background: Aurora-A (AURKA) belongs to the family of serine-threonine kinases that are crucial for cell cycle control. In particular, AURKA controls centrosome function, mitotic spindle formation, and proper chromosome segregation. In contrast to the well-defined function of AURKA in normal cells, the role of AURKA in malignant transformation and cancer progression is still under investigation. Here, we report that AURKA directly interacts with MEK1/2 kinase and induces chemotaxis of breast cancer cells. Results: We demonstrated that overexpression of AURKA in luminal ER+ MCF-7 cells (MCF-7AURKA) resulted in over 10-fold increase in the number of cells displaying chemotactic response upon stimulation with growth factors when compared to parental MCF-7 cells. Both AURKA inhibitor MLN8237 and MEK1/2 inhibitor PD0325901 reduced migratory properties of MCF-7AURKA cells. In contrast, treatment with the pan RAF inhibitor TAK-632 did not affect chemotactic response of MCF-7AURKA cells. We demonstrated colocalization of AURKA and MEK1/2 immunofluorescence signals in MCF-7AURKA and triple-negative BT549 cells. In situ proximity ligation assay (PLA) revealed the presence of AURKA-MEK1/2 complexes in MCF-7AURKA and BT549 cells, and the notion that AURKA and MEK1/2 formed cellular complexes was confirmed with co-immunoprecipitation experiments. In vitro kinase assays with recombinant AURKA and MEK1 proteins showed that AURKA kinase could directly phosphorylate MEK1. Incubation of MCF-7AURKA and BT549 cells with the AURKA-specific inhibitors MLN8237 or MK8745 resulted in over a 2-fold increase in the level of pERK1/2 compared to the untreated controls. Treatment with the pan RAF inhibitor TAK-632 did not diminish MLN8237-induced pERK1/2, whereas treatment with the MEK1/2 specific inhibitor PD0325901 completely abrogated MLN8237-induced activation of ERK1/2. Conclusions: Our data present a novel AURKA-MEK1/2 interaction that contributes to the increased chemotaxis of breast cancer cells. The results suggest that AURKA negatively regulates MEK1 through a novel, direct phosphorylation event, possibly leading to constitutive activation of MEK2 and increased chemotaxis. The combined treatment of AURKA and MEK1/2 inhibitors represents a new therapeutic approach to decrease metastatic potential of breast cancer cells and delay tumor progression. The in-depth analysis of the AURKA-MEK1/2 complexes as well as in vivo studies testing the efficacy of combining AURKA and MEK1/2 inhibitors on patient-derived xenografts are currently in progress. Citation Format: Malgorzata Gil, Archana Chidambaram, Thaer Khoury, Kazuaki Takabe, Igor Puzanov, Irwin H. Gelman, Antonino B. D’Assoro, Evanthia Galanis, Mateusz Opyrchal. AURKA interaction with MEK1/2 complex and its role in promoting breast cancer cell metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A60.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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