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Subcellular Localization of Total and Activated Src Kinase in African American and Caucasian Breast Cancer

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      Abstract

      Background

      Src, a non-receptor tyrosine kinase is elevated in cancer with expression and activity correlated with cell proliferation, adhesion, survival, motility, metastasis and angiogenesis. There is limited data on Src expression and subcellular localization in breast cancer and no information about expression in racial/ethnic groups.

      Methodology/Principal Findings

      The present study evaluated Src expression, activity, and subcellular localization in triple negative breast cancer (TNBC) and ERα positive breast cancer (ER+BC), cancer tissue and adjacent normal epithelial ducts, and Caucasian and African American cases. 79 paraffin embedded breast carcinoma cases were obtained from Tulane University Hospital between 2007–2009. 39 cases represented TNBC (33-African Americans, 4-Caucasians, 2-unknowns) and 40 cases represented ER+BC (21-African Americans, 16-Caucasians, 3-unknowns). Immunohistochemistry was used to measure staining distribution and intensity of total Src and activated phospho-SrcY416 (p-Y416Src) in carcinoma tissue and adjacent normal mammary ducts. In TNBC and ER+BC, total Src was significantly higher in cancer compared to adjacent normal ducts (P<0.0001) in both cell membrane and cytoplasm. In membranes, p-Y416Src was elevated in cancer compared to normal ducts. Total Src in the tumor cytoplasm was significantly higher in TNBC compared to ER+BC (P = 0.0028); conversely, p-Y416Src in the tumor cell membranes was higher in TNBC compared to ER+BC (P = 0.0106). Comparison between African American (n = 21) and Caucasian ER+BC (n = 16) revealed no significant difference in expression and localization of total Src and p-Y416Src. TNBC cases positive for lymph node metastasis showed elevated membrane p-Y416Src compared to lymph node negative TNBC (P = 0.027).

      Conclusion/Significance

      Total Src and p-Y416Src were expressed higher in cancer compared to adjacent normal ducts. Cytoplasmic total Src and membrane p-Y416Src were significantly higher in TNBC compared to ER+BC. TNBC cases with lymph node metastasis showed elevated membrane p-Y416Src. Taken together, Src was elevated in the membrane and cytoplasm of more aggressive TNBC.

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      Most cited references 41

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      Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.

      Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted "driver" signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.
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        Triple-negative breast cancer: clinical features and patterns of recurrence.

        To compare the clinical features, natural history, and outcomes for women with "triple-negative" breast cancer with women with other types of breast cancer. We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women's College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative. The prognostic significance of triple-negative breast cancer was explored. The median follow-up time of the 1,601 women was 8.1 years. One hundred and eighty of 1,601 patients (11.2%) had triple-negative breast cancer. Compared with other women with breast cancer, those with triple-negative breast cancer had an increased likelihood of distant recurrence (hazard ratio, 2.6; 95% confidence interval, 2.0-3.5; P < 0.0001) and death (hazard ratio, 3.2; 95% confidence interval, 2.3-4.5; P < 0.001) within 5 years of diagnosis but not thereafter. The pattern of recurrence was also qualitatively different; among the triple-negative group, the risk of distant recurrence peaked at approximately 3 years and declined rapidly thereafter. Among the "other" group, the recurrence risk seemed to be constant over the period of follow-up. Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.
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          The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes.

          Gene expression analysis identifies several breast cancer subtypes. We examined the relationship of neoadjuvant chemotherapy response to outcome among these breast cancer subtypes. We used immunohistochemical profiles [human epidermal growth factor receptor 2-positive (HER2+)/hormone receptor-negative for HER2+/estrogen receptor-negative (ER-), hormone receptor and HER2- for basal-like, hormone receptor-positive for luminal] to subtype a prospectively maintained data set of patients with breast cancer treated with neoadjuvant anthracycline-based (doxorubicin plus cyclophosphamide, AC) chemotherapy. We analyzed each subtype for clinical and pathologic response to neoadjuvant chemotherapy and examined the relationship of response to distant disease-free survival and overall survival. Of the 107 patients tested, 34 (32%) were basal-like, 11 (10%) were HER2+/ER-, and 62 (58%) were luminal. After neoadjuvant AC, 75% received subsequent chemotherapy and all received endocrine therapy if hormone receptor-positive. The chemotherapy regimen and pretreatment stage did not differ by subtype. Clinical response to AC was higher among the HER2+/ER- (70%) and basal-like (85%) than the luminal subtypes (47%; P < 0.0001). Pathologic complete response occurred in 36% of HER2+/ER-, 27% of basal-like, and 7% of luminal subtypes (P = 0.01). Despite initial chemosensitivity, patients with the basal-like and HER2+/ER- subtypes had worse distant disease-free survival (P = 0.04) and overall survival (P = 0.02) than those with the luminal subtypes. Regardless of subtype, only 2 of 17 patients with pathologic complete response relapsed. The worse outcome among basal-like and HER+/ER- subtypes was due to higher relapse among those with residual disease (P = 0.003). Basal-like and HER2+/ER- subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers. Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype. The poorer prognosis of basal-like and HER2+/ER- breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved.
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            Author and article information

            Affiliations
            [1 ]Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
            [2 ]Section of Surgical Pathology and Cytopathology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
            University of Texas Health Science Center at Houston, United States of America
            Author notes

            Conceived and designed the experiments: BGR MA KM. Performed the experiments: MA AA LC. Analyzed the data: BGR KM MA AA. Contributed reagents/materials/analysis tools: KM SG. Wrote the paper: MA BGR.

            Contributors
            Role: Editor
            Journal
            PLoS One
            PLoS ONE
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2012
            22 March 2012
            : 7
            : 3
            3310861
            22457730
            PONE-D-11-21438
            10.1371/journal.pone.0033017
            (Editor)
            Anbalagan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 10
            Categories
            Research Article
            Biology
            Histology
            Molecular Cell Biology
            Signal Transduction
            Medicine
            Oncology
            Cancer Risk Factors
            Cancers and Neoplasms
            Breast Tumors

            Uncategorized

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