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Carol A Sartorius - One of the best experts on this subject based on the ideXlab platform.
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abstract 2605 Cytokeratin 5 promotes endocytosis to remodel cell adhesions in breast cancer
Cancer Research, 2020Co-Authors: Olivia Mcginn, Jessica Finlayschultz, Ashley V. Ward, Kiran V. Paul, Peter Kabos, Carol A SartoriusAbstract:Breast cancer (BC) is clinically classified according to expression of estrogen receptor, progesterone receptor (ER+ BC), HER2 (HER2+), or absence of these markers (triple negative BC). While TNBC has the inferior prognosis in the short term, ER+ breast cancer has an extended risk of recurrence that lasts up to 20 years and accounts for the most deaths overall. Cytokeratin 5 (CK5) is an intermediate filament protein that is expressed in the majority of TNBC cases and 10-50% of ER+ BC. In CK5+/ER+ BC, there is widespread heterogeneity in the amount of CK5+ tumor cells (~1-50%). The mere presence of CK5+ cells is an indicator of poor prognosis across both subtypes of BC; the reasons for this are poorly understood. We have shown that CK5+ cells within ER+ and TNBC cell lines, and heterogeneous PDX tumor models lose membrane localization of adherens junction proteins β-catenin and E-cadherin. Loss of membrane β-catenin and E-cadherin is associated with poor prognosis in breast cancer and is a precursor to cell invasion. CK5+ cells have been reported to have increased invasive potential by us and others. Thus, identifying the mechanism of CK5-dependent loss of adherens proteins at the membrane could lead to development of therapies targeting this process. β-catenin and E-cadherin localization have been reported to be regulated through endocytosis which is mediated through the small GTPase family of Rab proteins. We performed a screen to identify potential CK5 interacting proteins in breast cancer cells and identified several Rab proteins. Thus, we hypothesizethat CK5 acts as a scaffold for Rabs to promote endocytosis of β-catenin and E-cadherin to increase invasive potential.To investigate this, we treated CK5 overexpressing ER+ and TNBC cells with the endocytosis inhibitor Dyngo4a and found membrane β-catenin and E-cadherin localization were restored, suggesting that CK5 may be mediating endocytosis of β-catenin and E-cadherin. Rab5 is responsible for trafficking vesicles from the plasma membrane to the early endosomes. CK5 was confirmed to interact with Rab5 by co-IP in TNBC and CK5 overexpressing ER+ cell lines. In ongoing studies, we are testing whether Rab5 knockdown prevents loss of membrane β-catenin and E-cadherin and decreases cell invasiveness. These experiments will collectively determine whether CK5 regulated endocytosis is a targetable feature in breast cancer cells. Citation Format: Olivia Frances McGinn, Ashley V. Ward, Jessica Finlay-Schultz, Kiran Vinod Paul, Peter Kabos, Carol Sartorius. Cytokeratin 5 promotes endocytosis to remodel cell adhesions in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2605.
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Cytokeratin 5 alters β-catenin dynamics in breast cancer cells
Oncogene, 2020Co-Authors: Olivia Mcginn, Ashley V. Ward, Lynsey M. Fettig, Duncan Riley, Joshua Ivie, Kiran V. Paul, Peter Kabos, Jessica Finlay-schultz, Carol A SartoriusAbstract:Estrogen receptor (ER) positive breast cancers often contain subpopulations of cells that express the intermediate filament protein Cytokeratin 5 (CK5). CK5+ cells are enriched in cancer stem cell (CSC) properties, can be induced by progestins, and predict poor prognosis in ER+ breast cancer. We established through CK5 knockout and overexpression in ER+ breast cancer cell lines that CK5 is important for tumorsphere formation, prompting us to speculate that CK5 has regulatory activity in CSCs. To interrogate CK5 interacting proteins that may be functionally cooperative, we performed immunoprecipitation-mass spectrometry for CK5 in ER+ breast cancer cells. Focusing on proteins with signaling activity, we identified β-catenin, a key transcription factor of the Wnt signaling pathway and cell adhesion molecule, as a CK5 interactor, which we confirmed by co-immunoprecipitation in several breast cancer models. We interrogated the dual functions of β-catenin in relation to CK5. Knockout or knockdown of CK5 ablated β-catenin transcriptional activity in response to progestins and Wnt stimuli. Conversely, CK5 induced by progestins or overexpression was sufficient to promote the loss of β-catenin at the cell membrane and total E-cadherin loss. A breast cancer patient-derived xenograft showed similar loss of membrane β-catenin and E-cadherin in CK5+ but not intratumoral CK5− cells and single-cell RNA sequencing found the top enriched pathways in the CK5+ cell cluster were cell junction remodeling and signaling. This report highlights that CK5 actively remodels cell morphology and that blockade of CK5-β-catenin interaction may reverse the detrimental properties of CK5+ breast cancer cells.
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Cytokeratin 5 positive cells represent a therapy resistant subpopulation in epithelial ovarian cancer
Gynecologic Oncology, 2015Co-Authors: Bradley R Corr, Jessica Finlayschultz, Rachel B Rosen, Lubna Qamar, Miriam D Post, Kian Behbakht, Monique A Spillman, Carol A SartoriusAbstract:Objective Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)+ breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5+ cell populations to cisplatin therapy. Materials and Methods Cytokeratin 5 expression was evaluated in 2 ovarian tissue microarrays, representing 137 neoplasms, and 6 ovarian cancer cell lines. Cell lines were treated with IC50 (half-maximal inhibitory concentration) cisplatin, and the prevalence of CK5+ cells pretreatment and posttreatment was determined. Proliferation of CK5+ versus CK5− cell populations was determined using 5-bromo-2′-deoxyuridine incorporation. Chemotherapy-induced apoptosis in CK5+ versus CK5− cells was measured using immunohistochemical staining for cleaved caspase-3. Results Cytokeratin 5 was expressed in 39.3% (42 of 107) of epithelial ovarian cancers with a range of 1% to 80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5+ specimens. Cytokeratin 5 expression correlated with ER positivity (38 of 42 CK5+ tumors were also ER+). Cytokeratin 5 was expressed in 5 of 6 overall and 4 of 4 ER+ epithelial ovarian cancer cell lines ranging from 2.4% to 52.7% positive cells. Cytokeratin 5+ compared with CK5− cells were slower proliferating. The prevalence of CK5+ cells increased after 48-hour cisplatin treatment in 4 of 5 cell lines tested. Cytokeratin 5+ ovarian cancer cells compared with CK5− ovarian cancer cells were more resistant to cisplatin-induced apoptosis. Conclusions Cytokeratin 5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating chemoresistant subpopulation that may warrant cotargeting in combination therapy.
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Progesterone-Inducible Cytokeratin 5-Positive Cells in Luminal Breast Cancer Exhibit Progenitor Properties
Hormones and Cancer, 2013Co-Authors: Sunshine Daddario Axlund, Rachel B Rosen, Peter Kabos, Byong Hoon Yoo, Jerome Schaack, Daniel V. Labarbera, Carol A SartoriusAbstract:Progestins play a deleterious role in the onset of breast cancer, yet their influence on existing breast cancer and tumor progression is not well understood. In luminal estrogen receptor (ER)- and progesterone receptor (PR)-positive breast cancer, progestins induce a fraction of cells to express Cytokeratin 5 (CK5), a marker of basal epithelial and progenitor cells in the normal breast. CK5^+ cells lose expression of ER and PR and are relatively quiescent, increasing their resistance to endocrine and chemotherapy compared to intratumoral CK5^−ER^+PR^+ cells. Characterization of live CK5^+ cells has been hampered by a lack of means for their direct isolation. Here, we describe optical (GFP) and bioluminescent (luciferase) reporter models to quantitate and isolate CK5^+ cells in luminal breast cancer cell lines utilizing the human KRT5 gene promoter and a viral vector approach. Using this system, we confirmed that the induction of GFP^+/CK5^+ cells is specific to progestins, is dependent on PR, can be blocked by antiprogestins, and does not occur with other steroid hormones. Progestin-induced, fluorescence-activated cell sorting-isolated CK5^+ cells had lower ER and PR mRNA, were slower cycling, and were relatively more invasive and sphere forming than their CK5^− counterparts in vitro. Repeated progestin treatment and selection of GFP^+ cells enriched for a persistent population of CK5^+ cells, suggesting that this transition can be semi-permanent. These data support that in PR^+ breast cancers, progestins induce a subpopulation of CK5^+ER^−PR^− cells with enhanced progenitor properties and have implications for treatment resistance and recurrence in luminal breast cancer.
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Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers
Breast Cancer Research and Treatment, 2011Co-Authors: Peter Kabos, James M Haughian, Xinshuo Wang, Christina Finlayson, Anthony D Elias, Kathryn B Horwitz, Carol A SartoriusAbstract:A majority of breast cancers are estrogen receptor (ER) positive and have a luminal epithelial phenotype. However, these ER+ tumors often contain heterogeneous subpopulations of ER− tumor cells. We previously identified a population of Cytokeratin 5 (CK5) positive cells within ER+ and progesterone receptor positive (PR+) tumors that is both ER−PR− and CD44+, a marker of breast tumor-initiating cells (TICs). These CK5+ cells have properties of TICs in luminal tumor xenografts, and we speculated that they are more resistant to chemo- and anti-ER-targeted therapies than their ER+ neighbors. To test this, we used ER+PR+ T47D and MCF7 breast cancer cells. CK5+ cells had lower proliferative indices than CK5− cells, were less sensitive to 5-fluorouracil and docetaxel, and cultures became enriched for CK5+ cells after treatments. CK5+ cells were less prone to drug-induced apoptosis than CK5− cells. In cells treated with 17β-estradiol (E) plus anti-estrogens tamoxifen or fulvestrant, ER protein levels decreased, and CK5 protein levels increased, compared to controls treated with E alone. In ER+ tumors from patients treated with neoadjuvant endocrine therapies ER gene expression decreased, and CK5 gene expression increased in post compared to pre-treatment tumors. The number of CK5+ cells in tumors also increased in post- compared to pre-treatment tumors. We conclude that an ER−PR−CK5+ subpopulation found in many luminal tumors is resistant to standard endocrine and chemotherapies, relative to the majority ER+PR+CK5− cells. Compounds that effectively target these cells are needed to improve outcome in luminal breast cancers.
A. R. Gibbs - One of the best experts on this subject based on the ideXlab platform.
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value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum
Histopathology, 2002Co-Authors: Richard Attanoos, R. Webb, S D Dojcinov, A. R. GibbsAbstract:Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum Aims: To evaluate the role of mesothelial markers (calretinin, thrombomodulin, Cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal carcinoembryonic antigen, Leu-M1, CA-125 and Ber-EP4) in distinguishing diffuse peritoneal malignant mesothelioma from primary serous papillary adenocarcinoma of the ovary and peritoneum. Methods and results: Paraffin-embedded formalin-fixed blocks from 32 diffuse peritoneal mesotheliomas of epithelial subtype (all females), 20 serous papillary ovarian carcinomas and three primary peritoneal serous papillary carcinomas were studied. Calretinin and Ber-EP4 appeared to be the best positive mesothelial and carcinoma marker, respectively. Nuclear calretinin expression was identified in 28 of 32 malignant mesotheliomas with no nuclear immunoreactivity in the cohorts of serous papillary ovarian and peritoneal carcinomas, thus yielding 88% sensitivity and 100% specificity. Ber-EP4 showed 95% sensitivity and 91% specificity for serous papillary ovarian carcin- oma. Thrombomodulin, Cytokeratin 5/6 and CD44H immunoreactivities were seen in 18 (56%), 17 (53%) and 15 (47%) of peritoneal mesotheliomas, respectively, and in six (30%), five (25%) and five (25%) of the ovarian tumours, respectively. None of the three primary peritoneal serous papillary carcinomas expressed calretinin, thrombomodulin, Cytokeratin 5/6 or CD44H. Polyclonal and monoclonal CEA, and Leu-M1 were expressed by two (10%), one (5%) and seven (35%) serous papillary ovarian carcinomas, respectively. None of the serous papillary peritoneal carcinomas expressed polyclonal CEA, monoclonal CEA or Leu-M1. CA-125 was positive in 19 (95%) and two (67%) ovarian and peritoneal carcinomas, respectively, and in eight (25%) peritoneal mesotheliomas. Conclusions: Calretinin and Ber-EP4 are useful discriminant markers in distinguishing peritoneal mesothelioma in women from serous papillary ovarian and peritoneal carcinoma. The other mesothelial markers (thrombomodulin, Cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal CEA, and Leu-M1) yielded a too low sensitivity for practical use.
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value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum
Histopathology, 2002Co-Authors: Richard Attanoos, R. Webb, S D Dojcinov, A. R. GibbsAbstract:AIMS: To evaluate the role of mesothelial markers (calretinin, thrombomodulin, Cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal carcinoembryonic antigen, Leu-M1, CA-125 and Ber-EP4) in distinguishing diffuse peritoneal malignant mesothelioma from primary serous papillary adenocarcinoma of the ovary and peritoneum. METHODS AND RESULTS: Paraffin-embedded formalin-fixed blocks from 32 diffuse peritoneal mesotheliomas of epithelial subtype (all females), 20 serous papillary ovarian carcinomas and three primary peritoneal serous papillary carcinomas were studied. Calretinin and Ber-EP4 appeared to be the best positive mesothelial and carcinoma marker, respectively. Nuclear calretinin expression was identified in 28 of 32 malignant mesotheliomas with no nuclear immunoreactivity in the cohorts of serous papillary ovarian and peritoneal carcinomas, thus yielding 88% sensitivity and 100% specificity. Ber-EP4 showed 95% sensitivity and 91% specificity for serous papillary ovarian carcinoma. Thrombomodulin, Cytokeratin 5/6 and CD44H immunoreactivities were seen in 18 (56%), 17 (53%) and 15 (47%) of peritoneal mesotheliomas, respectively, and in six (30%), five (25%) and five (25%) of the ovarian tumours, respectively. None of the three primary peritoneal serous papillary carcinomas expressed calretinin, thrombomodulin, Cytokeratin 5/6 or CD44H. Polyclonal and monoclonal CEA, and Leu-M1 were expressed by two (10%), one (5%) and seven (35%) serous papillary ovarian carcinomas, respectively. None of the serous papillary peritoneal carcinomas expressed polyclonal CEA, monoclonal CEA or Leu-M1. CA-125 was positive in 19 (95%) and two (67%) ovarian and peritoneal carcinomas, respectively, and in eight (25%) peritoneal mesotheliomas. CONCLUSIONS: Calretinin and Ber-EP4 are useful discriminant markers in distinguishing peritoneal mesothelioma in women from serous papillary ovarian and peritoneal carcinoma. The other mesothelial markers (thrombomodulin, Cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal CEA, and Leu-M1) yielded a too low sensitivity for practical use.
Richard Attanoos - One of the best experts on this subject based on the ideXlab platform.
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value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum
Histopathology, 2002Co-Authors: Richard Attanoos, R. Webb, S D Dojcinov, A. R. GibbsAbstract:Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum Aims: To evaluate the role of mesothelial markers (calretinin, thrombomodulin, Cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal carcinoembryonic antigen, Leu-M1, CA-125 and Ber-EP4) in distinguishing diffuse peritoneal malignant mesothelioma from primary serous papillary adenocarcinoma of the ovary and peritoneum. Methods and results: Paraffin-embedded formalin-fixed blocks from 32 diffuse peritoneal mesotheliomas of epithelial subtype (all females), 20 serous papillary ovarian carcinomas and three primary peritoneal serous papillary carcinomas were studied. Calretinin and Ber-EP4 appeared to be the best positive mesothelial and carcinoma marker, respectively. Nuclear calretinin expression was identified in 28 of 32 malignant mesotheliomas with no nuclear immunoreactivity in the cohorts of serous papillary ovarian and peritoneal carcinomas, thus yielding 88% sensitivity and 100% specificity. Ber-EP4 showed 95% sensitivity and 91% specificity for serous papillary ovarian carcin- oma. Thrombomodulin, Cytokeratin 5/6 and CD44H immunoreactivities were seen in 18 (56%), 17 (53%) and 15 (47%) of peritoneal mesotheliomas, respectively, and in six (30%), five (25%) and five (25%) of the ovarian tumours, respectively. None of the three primary peritoneal serous papillary carcinomas expressed calretinin, thrombomodulin, Cytokeratin 5/6 or CD44H. Polyclonal and monoclonal CEA, and Leu-M1 were expressed by two (10%), one (5%) and seven (35%) serous papillary ovarian carcinomas, respectively. None of the serous papillary peritoneal carcinomas expressed polyclonal CEA, monoclonal CEA or Leu-M1. CA-125 was positive in 19 (95%) and two (67%) ovarian and peritoneal carcinomas, respectively, and in eight (25%) peritoneal mesotheliomas. Conclusions: Calretinin and Ber-EP4 are useful discriminant markers in distinguishing peritoneal mesothelioma in women from serous papillary ovarian and peritoneal carcinoma. The other mesothelial markers (thrombomodulin, Cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal CEA, and Leu-M1) yielded a too low sensitivity for practical use.
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value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum
Histopathology, 2002Co-Authors: Richard Attanoos, R. Webb, S D Dojcinov, A. R. GibbsAbstract:AIMS: To evaluate the role of mesothelial markers (calretinin, thrombomodulin, Cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal carcinoembryonic antigen, Leu-M1, CA-125 and Ber-EP4) in distinguishing diffuse peritoneal malignant mesothelioma from primary serous papillary adenocarcinoma of the ovary and peritoneum. METHODS AND RESULTS: Paraffin-embedded formalin-fixed blocks from 32 diffuse peritoneal mesotheliomas of epithelial subtype (all females), 20 serous papillary ovarian carcinomas and three primary peritoneal serous papillary carcinomas were studied. Calretinin and Ber-EP4 appeared to be the best positive mesothelial and carcinoma marker, respectively. Nuclear calretinin expression was identified in 28 of 32 malignant mesotheliomas with no nuclear immunoreactivity in the cohorts of serous papillary ovarian and peritoneal carcinomas, thus yielding 88% sensitivity and 100% specificity. Ber-EP4 showed 95% sensitivity and 91% specificity for serous papillary ovarian carcinoma. Thrombomodulin, Cytokeratin 5/6 and CD44H immunoreactivities were seen in 18 (56%), 17 (53%) and 15 (47%) of peritoneal mesotheliomas, respectively, and in six (30%), five (25%) and five (25%) of the ovarian tumours, respectively. None of the three primary peritoneal serous papillary carcinomas expressed calretinin, thrombomodulin, Cytokeratin 5/6 or CD44H. Polyclonal and monoclonal CEA, and Leu-M1 were expressed by two (10%), one (5%) and seven (35%) serous papillary ovarian carcinomas, respectively. None of the serous papillary peritoneal carcinomas expressed polyclonal CEA, monoclonal CEA or Leu-M1. CA-125 was positive in 19 (95%) and two (67%) ovarian and peritoneal carcinomas, respectively, and in eight (25%) peritoneal mesotheliomas. CONCLUSIONS: Calretinin and Ber-EP4 are useful discriminant markers in distinguishing peritoneal mesothelioma in women from serous papillary ovarian and peritoneal carcinoma. The other mesothelial markers (thrombomodulin, Cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal CEA, and Leu-M1) yielded a too low sensitivity for practical use.
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anti mesothelial markers in sarcomatoid mesothelioma and other spindle cell neoplasms
Histopathology, 2000Co-Authors: Richard Attanoos, R. Webb, S D Dojcinov, Allen R GibbsAbstract:Aims To undertake a comparative evaluation of three antimesothelial markers (thrombomodulin, Cytokeratin 5/6 and calretinin) with broad spectrum Cytokeratin (AE1/AE3) in differentiating between sarcomatoid mesothelioma and a spectrum of spindle cell neoplasms. Methods and results Thirty-one malignant sarcomatoid mesotheliomas were studied. Calretinin expression was focally identified in 12 (39%) tumours and thrombomodulin and Cytokeratin 5/6 immunoreactivity was seen in nine (29%) cases. In comparison there was strong diffuse cytoplasmic reactivity with the broad spectrum Cytokeratin (AE1/AE3) in 24 of 31 (77%) tumours. Thirty mixed spindle cells neoplasms were studied. No calretinin expression was identified in any case. Thrombomodulin immunoreactivity was identified in four (16%) cases (two angiosarcomas, two high-grade sarcomas, not otherwise specified). Cytokeratin 5/6 expression was seen in one high-grade pulmonary sarcoma originally termed malignant fibrous histiocytoma. None of the antimesothelial markers was expressed in the four spindle cell carcinomas studied. In contrast, broad spectrum Cytokeratin was diffusely expressed in all four spindle cell carcinomas (three pulmonary, one renal), both synovial sarcomas, both malignant mixed Mullerian tumours, one of three pulmonary leiomyosarcomas and two of nine sarcomas, not otherwise specified. Conclusions Immunohistochemistry has a more limited role in the diagnosis and distinction of sarcomatoid mesothelioma from other spindle cell neoplasms. The combination of a broad spectrum Cytokeratin with calretinin combines both high sensitivity (77% for AE1/AE3) with high specificity (100% for calretinin) for sarcomatoid mesothelioma and can be diagnostically useful. The mesothelial markers, thrombomodulin and Cytokeratin 5/6, are not useful alone in the diagnosis of sarcomatoid mesothelioma as each shows insufficient antibody sensitivity, although together they complement calretinin.
Charles M Perou - One of the best experts on this subject based on the ideXlab platform.
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basal like breast cancer defined by five biomarkers has superior prognostic value than triple negative phenotype
Clinical Cancer Research, 2008Co-Authors: Maggie C U Cheang, Charles M Perou, David Voduc, Chris Bajdik, Samuel Leung, Steven Mckinney, Stephen Chia, Torsten O NielsenAbstract:Purpose: Basal-like breast cancer is associated with high grade, poor prognosis, and younger patient age. Clinically, a triple-negative phenotype definition [estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (HER)-2, all negative] is commonly used to identify such cases. EGFR and Cytokeratin 5/6 are readily available positive markers of basal-like breast cancer applicable to standard pathology specimens. This study directly compares the prognostic significance between three- and five-biomarker surrogate panels to define intrinsic breast cancer subtypes, using a large clinically annotated series of breast tumors. Experimental Design: Four thousand forty-six invasive breast cancers were assembled into tissue microarrays. All had staging, pathology, treatment, and outcome information; median follow-up was 12.5 years. Cox regression analyses and likelihood ratio tests compared the prognostic significance for breast cancer death-specific survival (BCSS) of the two immunohistochemical panels. Results: Among 3,744 interpretable cases, 17% were basal using the triple-negative definition (10-year BCSS, 6 7%) and 9% were basal using the five-marker method (10-year BCSS, 62%). Likelihood ratio tests of multivariable Cox models including standard clinical variables show that the five-marker panel is significantly more prognostic than the three-marker panel. The poor prognosis of triple-negative phenotype is conferred almost entirely by those tumors positive for basal markers. Among triple-negative patients treated with adjuvant anthracycline-based chemotherapy, the additional positive basal markers identified a cohort of patients with significantly worse outcome. Conclusions: The expanded surrogate immunopanel of estrogen receptor, progesterone receptor, human HER-2, EGFR, and Cytokeratin 5/6 provides a more specific definition of basal-like breast cancer that better predicts breast cancer survival.
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identification of a basal like subtype of breast ductal carcinoma in situ
Human Pathology, 2007Co-Authors: Chad A Livasy, Charles M Perou, Gamze Karaca, David Cowan, Diane M Maia, Susan A Jackson, Sarah J Nyante, Chiu Kit Tse, Robert C MillikanAbstract:Microarray profiling of invasive breast carcinomas has identified subtypes including luminal A, luminal B, HER2-overexpressing, and basal-like. The poor-prognosis, basal-like tumors have been immunohistochemically characterized as estrogen receptor (ER)-negative, HER2/neu-negative, and Cytokeratin 5/6-positive and/or epidermal growth factor receptor (EGFR)-positive. The aim of this study was to determine the prevalence of basal-like ductal carcinoma in situ in a population-based series of cases using immunohistochemical surrogates. A total of 245 pure ductal carcinoma in situ cases from a population-based, case-control study were evaluated for histologic characteristics and immunostained for ER, HER2/neu, EGFR, Cytokeratin 5/6, p53, and Ki-67. The subtypes were defined as: luminal A (ER+, HER2-), luminal B (ER+, HER2+), HER2 positive (ER-, HER2+), and basal-like (ER-, HER2-, EGFR+, and/or Cytokeratin 5/6+). The prevalence of breast cancer subtypes was basal-like (n = 19 [8%]); luminal A, n = 149 (61%); luminal B, n = 23 (9%); and HER2+/ER-, n = 38 (16%). Sixteen tumors (6%) were unclassified (negative for all 4 defining markers). The basal-like subtype was associated with unfavorable prognostic variables including high-grade nuclei (P < .0001), p53 overexpression (P < .0001), and elevated Ki-67 index (P < .0001). These studies demonstrate the presence of a basal-like in situ carcinoma, a potential precursor lesion to invasive basal-like carcinoma.
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identification of a basal like subtype of breast ductal carcinoma in situ
Human Pathology, 2007Co-Authors: Chad A Livasy, Charles M Perou, Gamze Karaca, David Cowan, Diane M Maia, Susan A Jackson, Sarah J Nyante, Robert C MillikanAbstract:Summary Microarray profiling of invasive breast carcinomas has identified subtypes including luminal A, luminal B, HER2-overexpressing, and basal-like. The poor-prognosis, basal-like tumors have been immunohistochemically characterized as estrogen receptor (ER)–negative, HER2/neu–negative, and Cytokeratin 5/6–positive and/or epidermal growth factor receptor (EGFR)–positive. The aim of this study was to determine the prevalence of basal-like ductal carcinoma in situ in a population-based series of cases using immunohistochemical surrogates. A total of 245 pure ductal carcinoma in situ cases from a population-based, case-control study were evaluated for histologic characteristics and immunostained for ER, HER2/neu, EGFR, Cytokeratin 5/6, p53, and Ki-67. The subtypes were defined as: luminal A (ER+, HER2−), luminal B (ER+, HER2+), HER2 positive (ER−, HER2+), and basal-like (ER−, HER2−, EGFR+, and/or Cytokeratin 5/6+). The prevalence of breast cancer subtypes was basal-like (n = 19 [8%]); luminal A, n=149 (61%); luminal B, n=23 (9%); and HER2+/ER−, n=38 (16%). Sixteen tumors (6%) were unclassified (negative for all 4 defining markers). The basal-like subtype was associated with unfavorable prognostic variables including high-grade nuclei ( P P P
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phenotypic evaluation of the basal like subtype of invasive breast carcinoma
Modern Pathology, 2006Co-Authors: Chad A Livasy, Gamze Karaca, Rita Nanda, Maria Tretiakova, Olufunmilayo I Olopade, Dominic T Moore, Charles M PerouAbstract:Microarray profiling of invasive breast carcinomas has identified five distinct subtypes of tumors (luminal A, luminal B, normal breast-like, HER2 overexpressing, and basal-like) that are associated with different clinical outcomes. The basal-like subtype is associated with poor clinical outcomes and is the subtype observed in BRCA1-related breast cancers. The aim of this study was to characterize the histologic and immunophenotypic properties of breast basal-like carcinomas that were first positively identified using DNA microarray analysis. Detailed histologic review was performed on 56 tumors with known microarray profiles (23 basal-like, 23 luminal, and 12 HER2+). Immunohistochemistry for estrogen receptor (ER), HER2, EGFR, smooth muscle actin (SMA), p63, CD10, Cytokeratin 5/6, Cytokeratin 8/18, and vimentin was performed on 18 basal-like, 16 luminal, and 12 HER2+ tumors. The basal-like tumors were grade 3 ductal/NOS (21/23) or metaplastic (2/23) carcinomas that frequently showed geographic necrosis (17/23), a pushing border of invasion (14/23), and a stromal lymphocytic response (13/23). Most basal-like tumors showed immunoreactivity for vimentin (17/18), luminal Cytokeratin 8/18 (15/18), EGFR (13/18), and Cytokeratin 5/6 (11/18), while positivity for the myoepithelial markers SMA (4/18), p63 (4/18) and CD10 (2/18) was infrequent. All basal-like tumors tested were ER- and HER2-. Morphologic features significantly associated with the basal-like subtype included markedly elevated mitotic count (P<0.0001), geographic tumor necrosis (P=0.0003), pushing margin of invasion (P=0.0001), and stromal lymphocytic response (P=0.01). The most consistent immunophenotype seen in the basal-like tumors was negativity for ER and HER2, and positivity for vimentin, EGFR, Cytokeratin 8/18, and Cytokeratin 5/6. The infrequent expression of myoepithelial markers in basal-like carcinomas does not support a direct myoepithelial cell derivation of these tumors. These findings should further assist in the identification of basal-like carcinomas in clinical specimens, facilitating treatment and epidemiologic studies of this tumor subtype.
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expression of Cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome
American Journal of Pathology, 2002Co-Authors: Matt Van De Rijn, Charles M Perou, Robert Tibshirani, Phillippe Haas, Olli Kallioniemi, Juha Kononen, J Torhorst, Guido Sauter, Markus Zuber, O R KochliAbstract:While several prognostic factors have been identified in breast carcinoma, the clinical outcome remains hard to predict for individual patients. Better predictive markers are needed to help guide difficult treatment decisions. In a previous study of 78 breast carcinoma specimens, we noted an association between poor clinical outcome and the expression of Cytokeratin 17 and/or Cytokeratin 5 mRNAs. Here we describe the results of immunohistochemistry studies using monoclonal antibodies against these markers to analyze more than 600 paraffin-embedded breast tumors in tissue microarrays. We found that expression of Cytokeratin 17 and/or Cytokeratin 5/6 in tumor cells was associated with a poor clinical outcome. Moreover, multivariate analysis showed that in node-negative breast carcinoma, expression of these Cytokeratins was a prognostic factor independent of tumor size and tumor grade.
Muhammad Muzzammil Edhi - One of the best experts on this subject based on the ideXlab platform.
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Cytokeratin 5 6 and Cytokeratin 8 18 expression in triple negative breast cancers clinicopathologic significance in south asian population
BMC Research Notes, 2018Co-Authors: Atif Ali Hashmi, Samreen Naz, Shumaila Kanwal Hashmi, Zubaida Fida Hussain, Muhammad Irfan, Naveen Faridi, Amir Nawaz Khan, Syed Muhammad Abu Bakar, Muhammad Muzzammil EdhiAbstract:Cytokeratin 5/6 and Cytokeratin 8/18 are basal and luminal markers of breast cancer and they have pathological and prognostic significance in breast cancer. We performed Cytokeratin 5/6 and CK8/18 immunohistochemistry on 150 cases of triple negative breast cancers and association with various clinicopathological features was evaluated. Positive CK5/6 expression was noted in 8% (12 cases) of TNBC while 2.4% (4 cases) showed focal positive (< 10%) and 89.3% (134) were negative with CK5/6. Complete loss of CK8/18 expression was seen in 4.7% (7 cases) while 32.7% (49 cases) revealed focal loss of CK8/18 and 62.7% (94 cases) showed intact normal expression of CK8/18. No significant association of CK5/6 and CK8/18 with various clinicopathological parameters was observed. We found a low expression of basal Cytokeratin (CK5/6) in TNBC our studied population, while loss/altered expression of CK8/18 in approximately 38% of TNBC. Although no prognostic relevance of these finding was noted in our study, however these findings are different from those reported in literature in other parts of the world. Therefore we suggest a more through immunohistochemical and genomic profiling of TNBC in our population for better understanding of this disease in this part of the world.
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Cytokeratin 5 6 expression in bladder cancer association with clinicopathologic parameters and prognosis
BMC Research Notes, 2018Co-Authors: Atif Ali Hashmi, Zubaida Fida Hussain, Muhammad Irfan, Naveen Faridi, Muhammad Muzzammil Edhi, Sarah Kanwal, Amir KhanAbstract:Well differentiated keratinized squamous component as a part of urothelial carcinoma can be easily appreciated; however non-keratinizing squamous differentiation closely resembles urothelial differentiation. In addition prognostic significance of CK 5/6 expression in the absence of apparent squamous differentiation is still unclear. Therefore, in the present study we aimed to evaluate the frequency of CK 5/6 expression in 127 cases of urothelial carcinoma and its prognostic significance in loco-regional population. Positive CK5/6 expression was noted in 6.3% (8 cases) and 13.4% (17 cases) revealed focal positive CK 5/6 expression. On the other hand, 80.3% (102 cases) showed negative CK5/6 staining. Significant association of CK5/6 expression was noted with tumor grade and muscularis propria invasion, however no significant association was noted with overall and disease free survival. On the basis of the results of our study we can conclude that CK5/6 is an independent prognostic biomarker in urothelial carcinoma and therefore can be used in the prognostic stratification of the patients with bladder cancer.
