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Shah S, Osuala KO, Brock EJ, Ji K, Sloane BF, Mattingly RR. Three-Dimensional Models: Biomimetic Tools That Recapitulate Breast Tissue Architecture and Microenvironment to Study Ductal Carcinoma In Situ Transition to Invasive Ductal Breast Cancer. Cells 2025; 14:220. [PMID: 39937011 PMCID: PMC11817749 DOI: 10.3390/cells14030220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Diagnosis of ductal carcinoma in situ (DCIS) presents a challenge as we cannot yet distinguish between those lesions that remain dormant from cases that may progress to invasive ductal breast cancer (IDC) and require therapeutic intervention. Our overall interest is to develop biomimetic three-dimensional (3D) models that more accurately recapitulate the structure and characteristics of pre-invasive breast cancer in order to study the underlying mechanisms driving malignant progression. These models allow us to mimic the microenvironment to investigate many aspects of mammary cell biology, including the role of the extracellular matrix (ECM), the interaction between carcinoma-associated fibroblasts (CAFs) and epithelial cells, and the dynamics of cytoskeletal reorganization. In this review article, we outline the significance of 3D culture models as reliable pre-clinical tools that mimic the in vivo tumor microenvironment and facilitate the study of DCIS lesions as they progress to invasive breast cancer. We also discuss the role of CAFs and other stromal cells in DCIS transition as well as the clinical significance of emerging technologies like tumor-on-chip and co-culture models.
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Affiliation(s)
- Seema Shah
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.S.); (E.J.B.)
| | | | - Ethan J. Brock
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.S.); (E.J.B.)
| | - Kyungmin Ji
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Bonnie F. Sloane
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.S.); (E.J.B.)
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Raymond R. Mattingly
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
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Sathvik G, V P, Joseph LD, Challa CB. Spectrum of Ductal Carcinoma In Situ (DCIS) Lesions of the Breast: From Morphology to Molecular Characteristics. Cureus 2024; 16:e69929. [PMID: 39439618 PMCID: PMC11495678 DOI: 10.7759/cureus.69929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/22/2024] [Indexed: 10/25/2024] Open
Abstract
Background Specific molecular characteristics of invasive breast cancer have been linked to an increased risk of early relapse. Similarly, ductal carcinoma in situ (DCIS) displays a comparable molecular profile, although their prevalence and implications are not yet fully understood. Aims and objectives The study design defined a multivariable statistical approach aimed at describing the interplay between the histopathological features of ductal carcinoma in situ (DCIS) and their molecular profile. The objective was to explore the correlations between the histopathological features of DCIS (tumor location, DCIS grade, DCIS type, and presence or absence of comedo necrosis) and various biomarkers like estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2/neu), androgen receptor (AR), and epidermal growth factor receptor (EGFR), in addition to the Ki-67 labeling index. Methods In this retrospective study, we selected and analyzed 100 diagnosed cases of ductal carcinoma in situ (DCIS) to represent various subtypes, grades, and morphological characteristics. A detailed histopathological review and immunohistopathological staining for ER, PR, HER2/neu, AR, EGFR, and Ki-67 were performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks. Molecular subtyping was done based on the biomarker analysis into luminal A, luminal B, luminal HER2/neu, HER2/neu enriched, and triple-negative subtypes. Statistical analysis was done to examine the correlation between tumor location, histopathological features of ductal carcinoma in situ (DCIS), and the expression of the immunohistochemical markers and the molecular subtypes. Results The majority of cases exhibited positivity for estrogen receptor (ER) and progesterone receptor (PR). A strong association was observed between histopathological features (DCIS grade, type, and comedo necrosis) of DCIS and ER/PR status. Additionally, a significant correlation was found between ductal carcinoma in situ (DCIS) grade and HER2/neu status. However, no association was identified between histopathological features and AR or EGFR status. Contrary to expectations, triple-negative DCIS did not show the most aggressive behavior, whereas HER2/neu-positive tumors, particularly high-grade ones, exhibited more aggressive features. No low-grade cases of luminal HER2/neu and HER2/neu-enriched tumors were found. A higher Ki-67 labeling index was found in cases with grade 3 and solid and comedo architectural types of DCIS, while low-grade tumors had a lower Ki-67 labeling index. Conclusion These findings suggest that hormone pathways play a crucial role in ductal carcinoma in situ (DCIS) progression, but the molecular interactions are complex and extend beyond simple binary associations. The complex relationship between the histopathological features of ductal carcinoma in situ (DCIS) and its hormone receptor status warrants further investigation with a larger sample size to fully understand the underlying mechanisms. The results challenge the expectation that triple-negative DCIS is the most aggressive subtype, highlighting the need for further research into the prognostic significance of different DCIS subtypes.
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Affiliation(s)
- Guttikonda Sathvik
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, IND
| | - Pavithra V
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, IND
| | - Leena D Joseph
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, IND
| | - Chithra Bhanu Challa
- Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, IND
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Kaplan HG, Dowdell AK, Berry AB, Shimol RB, Robinson FL, Carney CA, Piening BD. Multi-omic profiling of simultaneous ductal carcinoma in situ and invasive breast cancer. Breast Cancer Res Treat 2024; 205:451-464. [PMID: 38523186 PMCID: PMC11101558 DOI: 10.1007/s10549-024-07270-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 01/24/2024] [Indexed: 03/26/2024]
Abstract
PURPOSE The progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) in humans is highly variable. To better understand the relationship between them, we performed a multi-omic characterization of co-occurring DCIS and IBC lesions in a cohort of individuals. METHODS Formalin-fixed paraffin-embedded tissue samples from 50 patients with co-occurring DCIS and IBC lesions were subjected to DNA-seq and whole transcriptome RNA-seq. Paired DCIS and IBC multi-omics profiles were then interrogated for DNA mutations, gene expression profiles and pathway analysis. RESULTS Most small variants and copy number variations were shared between co-occurring DCIS and IBC lesions, with IBC exhibiting on average a higher degree of additional mutations. However, 36% of co-occurring lesions shared no common mutations and 49% shared no common copy number variations. The most frequent genomic variants in both DCIS and IBC were PIK3CA, TP53, KMT2C, MAP3K1, GATA3 and SF3B1, with KMT2C being more frequent in DCIS and TP53 and MAP3K1 more frequent in IBC, though the numbers are too small for definitive conclusions. The most frequent copy number variations were seen in MCL1, CKSB1 and ERBB2. ERBB2 changes were not seen in IBC unless present in the corresponding DCIS. Transcriptional profiles were highly distinct between DCIS and IBC, with DCIS exhibiting upregulation of immune-related signatures, while IBC showed significant overexpression in genes and pathways associated with cell division and proliferation. Interestingly, DCIS and IBC exhibited significant differential expression of different components of extracellular matrix (ECM) formation and regulation, with DCIS showing overexpression of ECM-membrane interaction components while IBC showed upregulation of genes associated with fibronectin and invadopodia. CONCLUSION While most co-occurring DCIS and IBC were mutationally similar and suggestive of a common clonal progenitor, transcriptionally the lesions are highly distinct, with IBC expressing key pathways that facilitate invasion and proliferation. These results are suggestive of additional levels of regulation, epigenetic or other, that facilitate the acquisition of invasive properties during tumor evolution.
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MESH Headings
- Humans
- Female
- Carcinoma, Intraductal, Noninfiltrating/genetics
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Mutation
- DNA Copy Number Variations
- Gene Expression Profiling/methods
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/metabolism
- Biomarkers, Tumor/genetics
- Middle Aged
- Neoplasm Invasiveness
- Gene Expression Regulation, Neoplastic
- Transcriptome
- Aged
- Adult
- Genomics/methods
- Multiomics
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Affiliation(s)
- Henry G Kaplan
- Swedish Cancer Institute, 1221 Madison St., Suite 920, Seattle, WA, 98104, USA.
| | - Alexa K Dowdell
- Earle A. Chiles Research Institute, Providence Health, Portland, OR, 97213, USA
| | - Anna B Berry
- Swedish Cancer Institute, 1221 Madison St., Suite 920, Seattle, WA, 98104, USA
| | - Racheli Ben Shimol
- Earle A. Chiles Research Institute, Providence Health, Portland, OR, 97213, USA
| | - Fred L Robinson
- Earle A. Chiles Research Institute, Providence Health, Portland, OR, 97213, USA
| | | | - Brian D Piening
- Earle A. Chiles Research Institute, Providence Health, Portland, OR, 97213, USA
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Rask G, Wadsten C, Acs B, Hartman J, Fredriksson I, Garmo H, Wärnberg F, Sund M. Immune cell infiltrate in ductal carcinoma in situ and the risk of dying from breast cancer: case-control study. Br J Surg 2024; 111:znae037. [PMID: 38395442 PMCID: PMC10890909 DOI: 10.1093/bjs/znae037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/25/2024] [Accepted: 02/01/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND Studies identifying risk factors for death from breast cancer after ductal carcinoma in situ (DCIS) are rare. In this retrospective nested case-control study, clinicopathological factors in women treated for DCIS and who died from breast cancer were compared with those of patients with DCIS who were free from metastatic disease. METHODS The study included patients registered with DCIS without invasive carcinoma in Sweden between 1992 and 2012. This cohort was linked to the National Cause of Death Registry. Of 6964 women with DCIS, 96 were registered with breast cancer as cause of death (cases). For each case, up to four controls (318; women with DCIS, alive and without metastatic breast cancer at the time of death of the corresponding case) were selected randomly by incidence density sampling. Whole slides of tumour tissue were evaluated for DCIS grade, comedo necrosis, and intensity of periductal lymphocytic infiltrate. Composition of the immune cell infiltrate, expression of oestrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and proliferation marker Ki-67 were scored on tissue microarrays. Clinical information was obtained from medical records. Information on date, site, and histological characteristics of local and distant recurrences was obtained from medical records for both cases and controls. RESULTS Tumour tissue was analysed from 65 cases and 195 controls. Intense periductal lymphocytic infiltrate around DCIS was associated with an increased risk of later dying from breast cancer (OR 2.21. 95% c.i. 1.01 to 4.84). Tumours with more intense lymphocytic infiltrate had a lower T cell/B cell ratio. None of the other biomarkers correlated with increased risk of breast cancer death. CONCLUSION The immune response to DCIS may influence the risk of dying from breast cancer.
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Affiliation(s)
- Gunilla Rask
- Department of Medical Biosciences/Pathology, Umeå University, Umeå, Sweden
- Department of Diagnostics and Intervention/Surgery, Umeå University, Umeå, Sweden
| | - Charlotta Wadsten
- Department of Diagnostics and Intervention/Surgery, Umeå University, Umeå, Sweden
- Department of Surgery, Sundsvall Hospital, Sundsvall, Sweden
| | - Balazs Acs
- Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
| | - Johan Hartman
- Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
| | - Irma Fredriksson
- Department of Breast, Endocrine Tumours and Sarcoma, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Hans Garmo
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
- Translational Oncology and Urology Research, King’s College London, London, UK
| | - Fredrik Wärnberg
- Department of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Malin Sund
- Department of Diagnostics and Intervention/Surgery, Umeå University, Umeå, Sweden
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Byon JH, Hwang S, Choi H, Choi EJ. Diagnostic Accuracy of Magnetic Resonance Imaging Features and Tumor-to-Nipple Distance for the Nipple-Areolar Complex Involvement of Breast Cancer: A Systematic Review and Meta-Analysis. Korean J Radiol 2023; 24:739-751. [PMID: 37500575 PMCID: PMC10400374 DOI: 10.3348/kjr.2022.0846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 05/02/2023] [Accepted: 05/19/2023] [Indexed: 07/29/2023] Open
Abstract
OBJECTIVE This systematic review and meta-analysis evaluated the accuracy of preoperative breast magnetic resonance imaging (MRI) features and tumor-to-nipple distance (TND) for diagnosing occult nipple-areolar complex (NAC) involvement in breast cancer. MATERIALS AND METHODS The MEDLINE, Embase, and Cochrane databases were searched for articles published until March 20, 2022, excluding studies of patients with clinically evident NAC involvement or those treated with neoadjuvant chemotherapy. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Two reviewers independently evaluated studies that reported the diagnostic performance of MRI imaging features such as continuity to the NAC, unilateral NAC enhancement, non-mass enhancement (NME) type, mass size (> 20 mm), and TND. Summary estimates of the sensitivity and specificity curves and the summary receiver operating characteristic (SROC) curve of the MRI features for NAC involvement were calculated using random-effects models. We also calculated the TND cutoffs required to achieve predetermined specificity values. RESULTS Fifteen studies (n = 4002 breast lesions) were analyzed. The pooled sensitivity and specificity (with 95% confidence intervals) for NAC involvement diagnosis were 71% (58-81) and 94% (91-96), respectively, for continuity to the NAC; 58% (45-70) and 97% (95-99), respectively, for unilateral NAC enhancement; 55% (46-64) and 83% (75-88), respectively, for NME type; and 88% (68-96) and 58% (40-75), respectively, for mass size (> 20 mm). TND had an area under the SROC curve of 0.799 for NAC involvement. A TND of 11.5 mm achieved a predetermined specificity of 85% with a sensitivity of 64%, and a TND of 12.3 mm yielded a predetermined specificity of 83% with a sensitivity of 65%. CONCLUSION Continuity to the NAC and unilateral NAC enhancement may help predict occult NAC involvement in breast cancer. To achieve the desired diagnostic performance with TND, a suitable cutoff value should be considered.
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Affiliation(s)
- Jung Hee Byon
- Department of Radiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Seungyong Hwang
- Department of Genetics, Stanford University, Stanford, CA, USA
| | - Hyemi Choi
- Department of Statistics and Institute of Applied Statistics, Jeonbuk National University, Jeonju, Republic of Korea.
| | - Eun Jung Choi
- Department of Radiology, Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, Republic of Korea.
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Schandiz H, Park D, Kaiser YL, Lyngra M, Talleraas IS, Geisler J, Sauer T. Subtypes of high-grade breast ductal carcinoma in situ (DCIS): incidence and potential clinical impact. Breast Cancer Res Treat 2023:10.1007/s10549-023-07016-9. [PMID: 37453021 PMCID: PMC10361903 DOI: 10.1007/s10549-023-07016-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
OBJECTIVE The purpose of this study was to investigate and classify the molecular subtypes of high-grade ductal carcinoma in situ (DCIS) and identify possible high-risk subtypes. The heterogenicity of DCIS with variable clinical and histopathological presentations has been recognized. Nevertheless, only histopathological grading and diameter are currently implemented in clinical decision-making following the diagnosis of DCIS. The molecular subtypes of DCIS and their IHC surrogate markers have not been defined in conventional treatment guidelines and recommendations. We applied the definitions of molecular subtypes according to the IHC surrogate markers defined for IBC and subclassified high-grade DCIS, accordingly. METHODS Histopathological specimens were collected, revised, and regraded from 494 patients diagnosed with DCIS between 1996 and 2018. Other in situ and papillary lesions observed in breast biopsies were excluded from this study. 357 high-grade DCIS cases were submitted to IHC analysis. The markers investigated were ER, PR, HER2, and Ki67. RESULTS 45 cases were classified as grade 1, 19 as grade 2, and 430 as grade 3. Sixty patients with high-grade DCIS had an additional invasive component in the surgical specimen. Thirty-three patients were diagnosed with recurrent DCIS or invasive cancer (minimum one year after their primary DCIS diagnosis). The proportions of luminal A and luminal B HER2-negative subtypes varied depending on whether 2011 or 2013 St. Gallen Consensus Conference guidelines were adopted. Luminal A was the most prevalent subtype, according to both classifications. The luminal B HER2-positive subtype was found in 22.1% of cases, HER2-enriched subtype in 21.8%, and TPN subtype in 5.6%. There were strong indications that HER2-enriched subtype was significantly more frequent among DCIS with invasive component (p = 0.0169). CONCLUSIONS High-grade DCIS exhibits all the molecular subtypes previously identified in IBC, but with a somewhat different distribution in our cohort. HER2-enriched subtype is substantially related to the presence of an invasive component in DCIS; consequently, it is regarded as a high-risk entity.
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Affiliation(s)
- Hossein Schandiz
- Department of Pathology, Akershus University Hospital, Lørenskog, Norway.
| | - Daehoon Park
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Yan Liu Kaiser
- Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital (AHUS), Lørenskog, Norway
| | - Marianne Lyngra
- Department of Pathology, Akershus University Hospital, Lørenskog, Norway
| | | | - Jürgen Geisler
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Campus AHUS, Oslo, Norway
| | - Torill Sauer
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Campus AHUS, Oslo, Norway
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Ji Y, Whitney HM, Li H, Liu P, Giger ML, Zhang X. Differences in Molecular Subtype Reference Standards Impact AI-based Breast Cancer Classification with Dynamic Contrast-enhanced MRI. Radiology 2023; 307:e220984. [PMID: 36594836 PMCID: PMC10068887 DOI: 10.1148/radiol.220984] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 10/20/2022] [Accepted: 11/01/2022] [Indexed: 01/04/2023]
Abstract
Background Breast cancer tumors can be identified as different luminal molecular subtypes depending on either immunohistochemical (IHC) staining or St Gallen criteria that includes Ki-67. Purpose To characterize molecular subtypes and understand the impact of disagreement among IHC and St Gallen molecular subtype reference standards on artificial intelligence classification of luminal A and luminal B tumors with use of radiomic features extracted from dynamic contrast-enhanced (DCE) MRI scans. Materials and Methods In this retrospective study, 28 radiomic features previously extracted from DCE-MRI scans of breast tumors imaged between February 2015 and October 2017 were examined in the following groups: (a) tumors classified as luminal A by both reference standards ("agreement"), (b) tumors classified as luminal A by IHC and luminal B by St Gallen ("disagreement"), and (c) tumors classified as luminal B by both ("agreement"). Luminal A or luminal B tumor classification with use of radiomic features was conducted with use of three sets: (a) IHC molecular subtyping, (b) St Gallen molecular subtyping, and (c) agreement tumors. The Kruskal-Wallis test was followed by the Mann-Whitney U test to determine pair-wise differences of radiomic features among agreement and disagreement tumors. Fivefold cross-validation with use of stepwise feature selection and linear discriminant analysis classified tumors in each set, with performance measured with use of area under the receiver operating characteristic curve (AUC). Results A total of 877 breast cancer tumors from 872 women (mean age, 48 years [range, 19-75 years]) were analyzed. Six features (sphericity, irregularity, surface area to volume ratio, variance of radial gradient histogram, sum average, volume of most enhancing voxels) were different (P ≤ .001) among agreement and disagreement tumors. AUC (median, 0.74 [95% CI: 0.68, 0.80]) was higher than when using tumors subtyped by either reference standard (IHC, 0.66 [0.60, 0.71], P = .003; St Gallen, 0.62 [0.58, 0.67], P = .001). Conclusion Differences in reference standards can hinder artificial intelligence classification performance of luminal molecular subtypes with dynamic contrast-enhanced MRI. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bae in this issue.
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Affiliation(s)
- Yu Ji
- From the Department of Radiology, The Second Hospital of Tianjin
Medical University, No. 23 Pingjiang Rd, Hexi District, Tianjin, China 300211
(Y.J., X.Z.); National Clinical Research Center for Cancer, Tianjin Medical
University Cancer Institute and Hospital, Tianjin, China (Y.J., P.L.);
Department of Radiology, The University of Chicago, Chicago, Ill (H.M.W., H.L.,
M.L.G.); and Department of Physics, Wheaton College, Wheaton, Ill
(H.M.W.)
| | - Heather M. Whitney
- From the Department of Radiology, The Second Hospital of Tianjin
Medical University, No. 23 Pingjiang Rd, Hexi District, Tianjin, China 300211
(Y.J., X.Z.); National Clinical Research Center for Cancer, Tianjin Medical
University Cancer Institute and Hospital, Tianjin, China (Y.J., P.L.);
Department of Radiology, The University of Chicago, Chicago, Ill (H.M.W., H.L.,
M.L.G.); and Department of Physics, Wheaton College, Wheaton, Ill
(H.M.W.)
| | - Hui Li
- From the Department of Radiology, The Second Hospital of Tianjin
Medical University, No. 23 Pingjiang Rd, Hexi District, Tianjin, China 300211
(Y.J., X.Z.); National Clinical Research Center for Cancer, Tianjin Medical
University Cancer Institute and Hospital, Tianjin, China (Y.J., P.L.);
Department of Radiology, The University of Chicago, Chicago, Ill (H.M.W., H.L.,
M.L.G.); and Department of Physics, Wheaton College, Wheaton, Ill
(H.M.W.)
| | - Peifang Liu
- From the Department of Radiology, The Second Hospital of Tianjin
Medical University, No. 23 Pingjiang Rd, Hexi District, Tianjin, China 300211
(Y.J., X.Z.); National Clinical Research Center for Cancer, Tianjin Medical
University Cancer Institute and Hospital, Tianjin, China (Y.J., P.L.);
Department of Radiology, The University of Chicago, Chicago, Ill (H.M.W., H.L.,
M.L.G.); and Department of Physics, Wheaton College, Wheaton, Ill
(H.M.W.)
| | - Maryellen L. Giger
- From the Department of Radiology, The Second Hospital of Tianjin
Medical University, No. 23 Pingjiang Rd, Hexi District, Tianjin, China 300211
(Y.J., X.Z.); National Clinical Research Center for Cancer, Tianjin Medical
University Cancer Institute and Hospital, Tianjin, China (Y.J., P.L.);
Department of Radiology, The University of Chicago, Chicago, Ill (H.M.W., H.L.,
M.L.G.); and Department of Physics, Wheaton College, Wheaton, Ill
(H.M.W.)
| | - Xuening Zhang
- From the Department of Radiology, The Second Hospital of Tianjin
Medical University, No. 23 Pingjiang Rd, Hexi District, Tianjin, China 300211
(Y.J., X.Z.); National Clinical Research Center for Cancer, Tianjin Medical
University Cancer Institute and Hospital, Tianjin, China (Y.J., P.L.);
Department of Radiology, The University of Chicago, Chicago, Ill (H.M.W., H.L.,
M.L.G.); and Department of Physics, Wheaton College, Wheaton, Ill
(H.M.W.)
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Gibson SV, Roozitalab RM, Allen MD, Jones JL, Carter EP, Grose RP. Everybody needs good neighbours: the progressive DCIS microenvironment. Trends Cancer 2023; 9:326-338. [PMID: 36739265 DOI: 10.1016/j.trecan.2023.01.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 02/05/2023]
Abstract
Ductal carcinoma in situ (DCIS) is a pre-invasive form of breast cancer where neoplastic luminal cells are confined to the ductal tree. While as many as 70% of DCIS cases will remain indolent, most women are treated with surgery, often combined with endocrine and radiotherapies. Overtreatment is therefore a major issue, demanding new methods to stratify patients. Somewhat paradoxically, the neoplastic cells in DCIS are genetically comparable to those in invasive disease, suggesting the tumour microenvironment is the driving force for progression. Clinical and mechanistic studies highlight the complex DCIS microenvironment, with multiple cell types competing to regulate progression. Here, we examine recent studies detailing distinct aspects of the DCIS microenvironment and discuss how these may inform more effective care.
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Affiliation(s)
- Shayin V Gibson
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Reza M Roozitalab
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Michael D Allen
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - J Louise Jones
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Edward P Carter
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
| | - Richard P Grose
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
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Gibson SV, Tomas Bort E, Rodríguez-Fernández L, Allen MD, Gomm JJ, Goulding I, Auf dem Keller U, Agnoletto A, Brisken C, Peck B, Cameron AJ, Marshall JF, Jones JL, Carter EP, Grose RP. TGFβ-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression. NPJ Breast Cancer 2023; 9:9. [PMID: 36864079 PMCID: PMC9981685 DOI: 10.1038/s41523-023-00513-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 02/15/2023] [Indexed: 03/04/2023] Open
Abstract
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Virtually all women with DCIS are treated, despite evidence suggesting up to half would remain with stable, non-threatening, disease. Overtreatment thus presents a pressing issue in DCIS management. To understand the role of the normally tumour suppressive myoepithelial cell in disease progression we present a 3D in vitro model incorporating both luminal and myoepithelial cells in physiomimetic conditions. We demonstrate that DCIS-associated myoepithelial cells promote striking myoepithelial-led invasion of luminal cells, mediated by the collagenase MMP13 through a non-canonical TGFβ - EP300 pathway. In vivo, MMP13 expression is associated with stromal invasion in a murine model of DCIS progression and is elevated in myoepithelial cells of clinical high-grade DCIS cases. Our data identify a key role for myoepithelial-derived MMP13 in facilitating DCIS progression and point the way towards a robust marker for risk stratification in DCIS patients.
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Affiliation(s)
- Shayin V Gibson
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Elena Tomas Bort
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Lucía Rodríguez-Fernández
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Michael D Allen
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Jennifer J Gomm
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Iain Goulding
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Ulrich Auf dem Keller
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Andrea Agnoletto
- ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole polytechnique fédérale de Lausanne (EPFL), SV2.832 Station 19, 1015, Lausanne, Switzerland
| | - Cathrin Brisken
- ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole polytechnique fédérale de Lausanne (EPFL), SV2.832 Station 19, 1015, Lausanne, Switzerland
| | - Barrie Peck
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Angus J Cameron
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - John F Marshall
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - J Louise Jones
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Edward P Carter
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
| | - Richard P Grose
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
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10
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Shams A. Re-evaluation of the myoepithelial cells roles in the breast cancer progression. Cancer Cell Int 2022; 22:403. [PMID: 36510219 PMCID: PMC9746125 DOI: 10.1186/s12935-022-02829-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Over the past decades, luminal epithelial cell lineage has gained considerable attraction as the functionally milk-secreting units and as the most fruitful acreage for breast cancer launching. Recognition of the effective involvement of the myoepithelial cells in mammary gland development and in hampering tumorigenesis has renewed the interest in investigating the biological roles of this second main mammary lineage. The human breast is made up of an extensively branching ductal system intervening by copious lobular units. The ductal system is coated by a chain of luminal epithelial cells (LECs) situated on a layer of myoepithelial cells (MECs) and encompassed by a distinguished basement membrane. Ductal contractility during lactation is a well-known function delivered by the MECs however this is not the only assignment mediated by these cellular populations. It has been well appreciated that the MECs exhibit a natural paracrine power in defeating cancer development and advancement. MECs were found to express numerous proteinase inhibitors, anti-angiogenic factors, and tumour suppressors proteins. Additionally, MECs contributed effectively to maintaining the right luminal cells' polarization and further separating them from the adjacent stroma by making an integrated fence. Indeed, disruption of the MECs layer was reported to facilitate the invasion of the cancer cells to the surrounding stroma. Nonetheless, MECs were also found to exhibit cancer-promoting effects and provoke tumour invasion and dissemination by displaying distinct cancer chemokines. Herein in this review, we aimed to address the roles delivered by MECs in breast cancer progression and decipher the molecular mechanisms regulating proper MECs' physiology, integrity, and terminal differentiation.
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Affiliation(s)
- Anwar Shams
- grid.412895.30000 0004 0419 5255Department of Pharmacology, College of Medicine, Taif University, P.O. BOX 11099, Taif, 21944 Saudi Arabia
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11
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Dawoud MM, Jones DT, Chelala C, Abdou AG, Dreger SA, Asaad N, Abd El-Wahed M, Jones L. Expression Profile of Myoepithelial Cells in DCIS: Do They Change From Protective Angels to Wicked Witches? Appl Immunohistochem Mol Morphol 2022; 30:397-409. [PMID: 35467556 DOI: 10.1097/pai.0000000000001028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 02/18/2022] [Indexed: 11/02/2022]
Abstract
The mechanism of transition of ductal carcinoma in situ (DCIS) to invasive cancer is elusive but recently changes in the myoepithelial cells (MECs) have been implicated. The aim of this study is to investigate the changes in gene profile of MECs in DCIS that could compromise their tumor suppressor function leading to promotion of tumor progression. Immuno-laser capture microdissection (LCM) was used to isolate MECs from normal and DCIS breast tissues followed by whole genome expression profiling using Affymetrix HGU-133 plus2.0 arrays. The data were analyzed using Bioconductor packages then validated by using real-time quantitative polymerase chain reaction and immunohistochemistry. Ingenuity Pathways software analysis showed clustering of most of the altered genes in cancer and cell death networks, with the Wnt/B-catenin pathway as the top canonical pathway. Validation revealed a 71.4% correlation rate with the array results. Most dramatic was upregulation of Fibronectin 1 ( FN1 ) in DCIS-associated MECs. Immunohistochemistry analysis for FN1 on normal and DCIS tissues confirmed a strong correlation between FN1 protein expression by MECs and DCIS ( P <0.0001) and between high expression level and presence of invasion ( P =0.006) in DCIS. Other validated alterations in MEC expression profile included upregulation of Nephronectin and downregulation of parathyroid hormone like hormone ( PTHLH ), fibroblast growth factor receptor 2 ( FGFR2 ), ADAMTS5 , TGFBR3 , and CAV1 . In vitro experiments revealed downregulation of PTHLH in DCIS-modified MECs versus normal lines when cultured on Fibronectin matrix. This is the first study to use this in vivo technique to investigate molecular changes in MECs in DCIS. This study adds more evidences to the molecular deviations in MECs toward tumor progression in DCIS through upregulation of the tumor-promoting molecules that may lead to novel predictive and therapeutic targets.
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Affiliation(s)
- Marwa M Dawoud
- Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Dylan T Jones
- Centre for Tumour Biology, Institute of Cancer & CR-UK Clinical Centre, Barts and The London School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ
| | - Claude Chelala
- Centre for Tumour Biology, Institute of Cancer & CR-UK Clinical Centre, Barts and The London School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ
| | - Asmaa G Abdou
- Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Sally A Dreger
- Centre for Tumour Biology, Institute of Cancer & CR-UK Clinical Centre, Barts and The London School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ
- Gut Microbes in Health, Quadram Institute Bioscience, Norwich, UK
| | - Nancy Asaad
- Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | | | - Louise Jones
- Centre for Tumour Biology, Institute of Cancer & CR-UK Clinical Centre, Barts and The London School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ
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12
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Chen XY, Yung LYL, Tan PH, Bay BH. Harnessing the Immunogenic Potential of Gold Nanoparticle-Based Platforms as a Therapeutic Strategy in Breast Cancer Immunotherapy: A Mini Review. Front Immunol 2022; 13:865554. [PMID: 35432376 PMCID: PMC9008216 DOI: 10.3389/fimmu.2022.865554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/14/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer remains the most common malignancy among women worldwide. Although the implementation of mammography has dramatically increased the early detection rate, conventional treatments like chemotherapy, radiation therapy, and surgery, have significantly improved the prognosis for breast cancer patients. However, about a third of treated breast cancer patients are known to suffer from disease recurrences and progression to metastasis. Immunotherapy has recently gained traction due to its ability to establish long-term immune surveillance, and response for the prevention of disease recurrence and extension of patient survival. Current research findings have revealed that gold nanoparticles can enhance the safety and efficacy of cancer immunotherapy, through their unique intrinsic properties of good biocompatibility, durability, convenient surface modification, as well as enhanced permeability and retention effect. Gold nanoparticles are also able to induce innate immune responses through the process of immunogenic cell death, which can lead to the establishment of lasting adaptive immunity. As such gold nanoparticles are considered as good candidates for next generation immunotherapeutic strategies. This mini review gives an overview of gold nanoparticles and their potential applications in breast cancer immunotherapeutic strategies.
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Affiliation(s)
- Xiao-Yang Chen
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Lin-Yue Lanry Yung
- Department of Biomolecular and Chemical Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore
| | - Puay Hoon Tan
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Pathology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Boon Huat Bay
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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13
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Pangeni RP, Olivaries I, Huen D, Buzatto VC, Dawson TP, Ashton KM, Davis C, Brodbelt AR, Jenkinson MD, Bièche I, Yang L, Latif F, Darling JL, Warr TJ, Morris MR. Genome-wide methylation analyses identifies Non-coding RNA genes dysregulated in breast tumours that metastasise to the brain. Sci Rep 2022; 12:1102. [PMID: 35058523 PMCID: PMC8776809 DOI: 10.1038/s41598-022-05050-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Brain metastases comprise 40% of all metastatic tumours and breast tumours are among the tumours that most commonly metastasise to the brain, the role that epigenetic gene dysregulation plays in this process is not well understood. We carried out 450 K methylation array analysis to investigate epigenetically dysregulated genes in breast to brain metastases (BBM) compared to normal breast tissues (BN) and primary breast tumours (BP). For this, we referenced 450 K methylation data for BBM tumours prepared in our laboratory with BN and BP from The Cancer Genome Atlas. Experimental validation on our initially identified genes, in an independent cohort of BP and in BBM and their originating primary breast tumours using Combined Bisulphite and Restriction Analysis (CoBRA) and Methylation Specific PCR identified three genes (RP11-713P17.4, MIR124-2, NUS1P3) that are hypermethylated and three genes (MIR3193, CTD-2023M8.1 and MTND6P4) that are hypomethylated in breast to brain metastases. In addition, methylation differences in candidate genes between BBM tumours and originating primary tumours shows dysregulation of DNA methylation occurs either at an early stage of tumour evolution (in the primary tumour) or at a later evolutionary stage (where the epigenetic change is only observed in the brain metastasis). Epigentic changes identified could also be found when analysing tumour free circulating DNA (tfcDNA) in patient’s serum taken during BBM biopsies. Epigenetic dysregulation of RP11-713P17.4, MIR3193, MTND6P4 are early events suggesting a potential use for these genes as prognostic markers.
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14
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Agahozo MC, Smid M, van Marion R, Hammerl D, van den Bosch TPP, Timmermans MAM, Heijerman CJ, Westenend PJ, Debets R, Martens JWM, van Deurzen CHM. Transcriptomic Properties of HER2+ Ductal Carcinoma In Situ of the Breast Associate with Absence of Immune Cells. BIOLOGY 2021; 10:768. [PMID: 34440000 PMCID: PMC8389698 DOI: 10.3390/biology10080768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 11/16/2022]
Abstract
The identification of transcriptomic alterations of HER2+ ductal carcinoma in situ (DCIS) that are associated with the density of tumor-infiltrating lymphocytes (TILs) could contribute to optimizing choices regarding the potential benefit of immune therapy. We compared the gene expression profile of TIL-poor HER2+ DCIS to that of TIL-rich HER2+ DCIS. Tumor cells from 11 TIL-rich and 12 TIL-poor DCIS cases were micro-dissected for RNA isolation. The Ion AmpliSeq Transcriptome Human Gene Expression Kit was used for RNA sequencing. After normalization, a Mann-Whitney rank sum test was used to analyze differentially expressed genes between TIL-poor and TIL-rich HER2+ DCIS. Whole tissue sections were immunostained for validation of protein expression. We identified a 29-gene expression profile that differentiated TIL-rich from TIL-poor HER2+ DCIS. These genes included CCND3, DUSP10 and RAP1GAP, which were previously described in breast cancer and cancer immunity and were more highly expressed in TIL-rich DCIS. Using immunohistochemistry, we found lower protein expression in TIL-rich DCIS. This suggests regulation of protein expression at the posttranslational level. We identified a gene expression profile of HER2+ DCIS cells that was associated with the density of TILs. This classifier may guide towards more rationalized choices regarding immune-mediated therapy in HER2+ DCIS, such as targeted vaccine therapy.
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Affiliation(s)
- Marie Colombe Agahozo
- Department of Pathology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.C.A.); (R.v.M.); (T.P.P.v.d.B.)
| | - Marcel Smid
- Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.S.); (D.H.); (M.A.M.T.); (C.J.H.); (R.D.); (J.W.M.M.)
| | - Ronald van Marion
- Department of Pathology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.C.A.); (R.v.M.); (T.P.P.v.d.B.)
| | - Dora Hammerl
- Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.S.); (D.H.); (M.A.M.T.); (C.J.H.); (R.D.); (J.W.M.M.)
| | - Thierry P. P. van den Bosch
- Department of Pathology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.C.A.); (R.v.M.); (T.P.P.v.d.B.)
| | - Mieke A. M. Timmermans
- Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.S.); (D.H.); (M.A.M.T.); (C.J.H.); (R.D.); (J.W.M.M.)
| | - Chayenne J. Heijerman
- Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.S.); (D.H.); (M.A.M.T.); (C.J.H.); (R.D.); (J.W.M.M.)
| | | | - Reno Debets
- Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.S.); (D.H.); (M.A.M.T.); (C.J.H.); (R.D.); (J.W.M.M.)
| | - John W. M. Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.S.); (D.H.); (M.A.M.T.); (C.J.H.); (R.D.); (J.W.M.M.)
| | - Carolien H. M. van Deurzen
- Department of Pathology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands; (M.C.A.); (R.v.M.); (T.P.P.v.d.B.)
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15
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Pedroza DA, Ramirez M, Rajamanickam V, Subramani R, Margolis V, Gurbuz T, Estrada A, Lakshmanaswamy R. miRNome and Functional Network Analysis of PGRMC1 Regulated miRNA Target Genes Identify Pathways and Biological Functions Associated With Triple Negative Breast Cancer. Front Oncol 2021; 11:710337. [PMID: 34350123 PMCID: PMC8327780 DOI: 10.3389/fonc.2021.710337] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 06/24/2021] [Indexed: 12/14/2022] Open
Abstract
Background Increased expression of the progesterone receptor membrane component 1, a heme and progesterone binding protein, is frequently found in triple negative breast cancer tissue. The basis for the expression of PGRMC1 and its regulation on cellular signaling mechanisms remain largely unknown. Therefore, we aim to study microRNAs that target selective genes and mechanisms that are regulated by PGRMC1 in TNBCs. Methods To identify altered miRNAs, whole human miRNome profiling was performed following AG-205 treatment and PGRMC1 silencing. Network analysis identified miRNA target genes while KEGG, REACTOME and Gene ontology were used to explore altered signaling pathways, biological processes, and molecular functions. Results KEGG term pathway analysis revealed that upregulated miRNAs target specific genes that are involved in signaling pathways that play a major role in carcinogenesis. While multiple downregulated miRNAs are known oncogenes and have been previously demonstrated to be overexpressed in a variety of cancers. Overlapping miRNA target genes associated with KEGG term pathways were identified and overexpression/amplification of these genes was observed in invasive breast carcinoma tissue from TCGA. Further, the top two genes (CCND1 and YWHAZ) which are highly genetically altered are also associated with poorer overall survival. Conclusions Thus, our data demonstrates that therapeutic targeting of PGRMC1 in aggressive breast cancers leads to the activation of miRNAs that target overexpressed genes and deactivation of miRNAs that have oncogenic potential.
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Affiliation(s)
- Diego A Pedroza
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Matthew Ramirez
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Venkatesh Rajamanickam
- Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States
| | - Ramadevi Subramani
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States.,Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Victoria Margolis
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Tugba Gurbuz
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Adriana Estrada
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Rajkumar Lakshmanaswamy
- Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States.,Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
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16
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van Seijen M, Jóźwiak K, Pinder SE, Hall A, Krishnamurthy S, Thomas JSJ, Collins LC, Bijron J, Bart J, Cohen D, Ng W, Bouybayoune I, Stobart H, Hudecek J, Schaapveld M, Thompson A, Lips EH, Wesseling J. Variability in grading of ductal carcinoma in situ among an international group of pathologists. J Pathol Clin Res 2021; 7:233-242. [PMID: 33620141 PMCID: PMC8073001 DOI: 10.1002/cjp2.201] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 12/11/2020] [Accepted: 01/08/2021] [Indexed: 01/04/2023]
Abstract
The prognostic value of cytonuclear grade in ductal carcinoma in situ (DCIS) is debated, partly due to high interobserver variability and the use of multiple guidelines. The aim of this study was to evaluate interobserver agreement in grading DCIS between Dutch, British, and American pathologists. Haematoxylin and eosin-stained slides of 425 women with primary DCIS were independently reviewed by nine breast pathologists based in the Netherlands, the UK, and the USA. Chance-corrected kappa (κma ) for association between pathologists was calculated based on a generalised linear mixed model using the ordinal package in R. Overall κma for grade of DCIS (low, intermediate, or high) was estimated to be 0.50 (95% confidence interval [CI] 0.44-0.56), indicating a moderate association between pathologists. When the model was adjusted for national guidelines, the association for grade did not change (κma = 0.53; 95% CI 0.48-0.57); subgroup analysis for pathologists using the UK pathology guidelines only had significantly higher association (κma = 0.58; 95% CI 0.56-0.61). To assess if concordance of grading relates to the expression of the oestrogen receptor (ER) and HER2, archived immunohistochemistry was analysed on a subgroup (n = 106). This showed that non-high grade according to the majority opinion was associated with ER positivity and HER2 negativity (100 and 89% of non-high grade cases, respectively). In conclusion, DCIS grade showed only moderate association using whole slide images scored by nine breast pathologists. As therapeutic decisions and inclusion in ongoing clinical trials are guided by DCIS grade, there is a pressing need to reduce interobserver variability in grading. ER and HER2 might be supportive to prevent the accidental and unwanted inclusion of high-grade DCIS in such trials.
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Affiliation(s)
- Maartje van Seijen
- Division of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Katarzyna Jóźwiak
- Division of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
- Institute of Biostatistics and Registry ResearchBrandenburg Medical School Theodor FontaneNeuruppinGermany
| | - Sarah E Pinder
- Comprehensive Cancer Centre at Guy's Hospital, School of Cancer & Pharmaceutical SciencesKings College LondonLondonUK
- Department of Cellular PathologyGuy's and St Thomas' NHS Foundation Trust LondonLondonUK
| | - Allison Hall
- Department of PathologyDuke University Medical CenterDurhamNCUSA
| | - Savitri Krishnamurthy
- Department of PathologyThe University of Texas MD Anderson Cancer CenterHoustonTXUSA
| | | | - Laura C Collins
- Department of PathologyBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMAUSA
| | - Jonathan Bijron
- Department of PathologyMartini HospitalGroningenThe Netherlands
| | - Joost Bart
- Department of PathologyIsala HospitalZwolleThe Netherlands
- Department of PathologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Danielle Cohen
- Department of PathologyLeiden University Medical CenterLeidenThe Netherlands
| | - Wen Ng
- Department of Cellular PathologyGuy's and St Thomas' NHS Foundation Trust LondonLondonUK
| | - Ihssane Bouybayoune
- Comprehensive Cancer Centre at Guy's Hospital, School of Cancer & Pharmaceutical SciencesKings College LondonLondonUK
| | | | - Jan Hudecek
- Department of Research ITThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Michael Schaapveld
- Department of Psychosocial Research and EpidemiologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Alastair Thompson
- Dan L Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTXUSA
| | - Esther H Lips
- Division of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
| | - Jelle Wesseling
- Division of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
- Department of PathologyIsala HospitalZwolleThe Netherlands
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17
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Tiwari S, Yang J, Morisseau C, Durbin-Johnson B, Hammock BD, Gomes AV. Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers. Sci Rep 2021; 11:7042. [PMID: 33782432 PMCID: PMC8007717 DOI: 10.1038/s41598-021-86284-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 03/11/2021] [Indexed: 11/09/2022] Open
Abstract
Over the last decade oxylipins have become more recognized for their involvement in several diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are known to inhibit cyclooxygenase (COX) enzymes, but how NSAIDs affect oxylipins, in addition to COX products, in animal tissues is not well understood. Oxylipins in livers from male and female mice treated with 100 mg/kg/day of ibuprofen for 7 days were investigated. The results showed that ibuprofen treated male livers contained 7 times more altered oxylipins than ibuprofen treated female livers. In male and female livers some prostaglandins were altered, while diols, hydroxy fatty acids and epoxides were significantly altered in male livers. Some soluble epoxide hydrolase (sEH) products, such as 9,10-DiHODE were found to be decreased, while sEH substrates (such as 9(10)-EpODE and 5(6)-EpETrE) were found to be increased in male livers treated with ibuprofen, but not in ibuprofen treated female livers. The enzymatic activities of sEH and microsomal epoxide hydrolase (mEH) were elevated by ibuprofen in both males and females. Analyzing the influence of sex on the effect of ibuprofen on oxylipins and COX products showed that approximately 27% of oxylipins detected were influenced by sex. The results reveal that ibuprofen disturbs not only the COX pathway, but also the CYP450 and lipoxygenase pathways in male mice, suggesting that ibuprofen is likely to generate sex related differences in biologically active oxylipins. Increased sEH activity after ibuprofen treatment is likely to be one of the mechanisms by which the liver reduces the higher levels of EpODEs and EpETrEs.
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Affiliation(s)
- Shuchita Tiwari
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA, 95616, USA
| | - Jun Yang
- Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, 95616, USA
| | - Christophe Morisseau
- Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, 95616, USA
| | | | - Bruce D Hammock
- Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, 95616, USA
| | - Aldrin V Gomes
- Department of Neurobiology, Physiology, and Behavior, University of California, Davis, CA, 95616, USA. .,Department of Physiology and Membrane Biology, University of California, Davis, CA, USA.
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18
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Stanciu-Pop C, Nollevaux MC, Berlière M, Duhoux FP, Fellah L, Galant C, Van Bockstal MR. Morphological intratumor heterogeneity in ductal carcinoma in situ of the breast. Virchows Arch 2021; 479:33-43. [PMID: 33502600 DOI: 10.1007/s00428-021-03040-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 01/08/2021] [Accepted: 01/20/2021] [Indexed: 11/28/2022]
Abstract
Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous disease in terms of morphological characteristics, protein expression profiles, genetic abnormalities, and potential for progression. Molecular heterogeneity has been extensively studied in DCIS. Yet morphological heterogeneity remains relatively undefined. This study investigated morphological intratumor heterogeneity in a series of 51 large DCIS. Nuclear atypia, DCIS architecture, necrosis, calcifications, stromal architecture, and stromal inflammation were assessed in one biopsy slide and three representative slides from each corresponding resection. For each histopathological feature, a histo-score was determined per slide and compared between the biopsy and the resection, as well as within a single resection. Statistical analysis comprised of Friedman tests, post hoc Wilcoxon tests with Bonferroni corrections, Mann-Whitney U tests, and chi-square tests. Despite substantial morphological heterogeneity in around 50% of DCIS, the histopathological assessment of the biopsy did not statistically significantly differ from the resection. Morphological heterogeneity was not significantly associated with patient age, DCIS size, or type of surgery, except for a weak association between heterogeneous stromal inflammation and smaller DCIS size. At the group level, the degree of heterogeneity did not significantly affect the representativity of a biopsy. At the individual patient level, however, the presence of necrosis, intraductal calcifications, myxoid stromal changes, and high-grade nuclear atypia was underestimated in a minority of DCIS patients. This study confirms the presence of morphological heterogeneity in DCIS for all six evaluated histopathological features. This should be kept in mind when taking biopsy-based treatment decisions for DCIS patients.
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Affiliation(s)
- Claudia Stanciu-Pop
- Department of Pathology, CHU UCL Namur, Site Godinne, Avenue Docteur G. Thérasse 1, 5530, Yvoir, Belgium
| | - Marie-Cécile Nollevaux
- Department of Pathology, CHU UCL Namur, Site Godinne, Avenue Docteur G. Thérasse 1, 5530, Yvoir, Belgium
| | - Martine Berlière
- Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.,Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium
| | - Francois P Duhoux
- Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.,Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium.,Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium
| | - Latifa Fellah
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium.,Department of Radiology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium
| | - Christine Galant
- Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.,Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium.,Department of Pathology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium
| | - Mieke R Van Bockstal
- Breast Clinic, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium. .,Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Avenue Hippocrate 10, 1200, Brussels, Belgium. .,Department of Pathology, Cliniques universitaires Saint-Luc, Avenue Hippocrate 10, 1200, Brussels, Belgium.
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19
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Yang L, Lu D, Lai Y, Shen M, Yu Q, Lei T, Pu T, Bu H. Prognostic Score-Based Stratification Analysis Reveals Universal Benefits of Radiotherapy on Lowering the Risk of Ipsilateral Breast Event for Ductal Carcinoma In Situ Patients with Different Risk Levels. Ann Surg Oncol 2020; 28:975-984. [PMID: 32794031 DOI: 10.1245/s10434-020-09003-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 07/21/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND We aimed to analyze the effects of radiotherapy (RT) on the incidence rate of ipsilateral breast event (IBE) in ductal carcinoma in situ (DCIS) patients with lumpectomy after being stratified by prognostic score. METHODS We identified DCIS patients who received lumpectomy, from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2015. Cumulative incidence functions for competing risk were used to evaluate the effects of RT on IBE risk over time. Three multivariate regression models (weighted, non-weighted, and Fine-Gray) were applied to compare the IBE risk between the RT and non-RT groups after stratifying patients by prognostic score. RESULTS Overall, 72,623 DCIS patients were identified from the SEER database and 49,206 (66.8%) patients received RT. During the follow-up period (ranging from 7 to 347 months), the cumulative probability of invasive and in situ IBE was significantly lower in the RT group than in the non-RT group (p < 0.001). After being stratified by prognostic score, the weighted IBE incidence rate increased as the risk level increased (p < 0.050). In multivariate regression models, RT lowered the IBE incidence rate by at least 30% in low-, moderate-, and high-risk DCIS (p < 0.010). In particular, the in situ and invasive IBE incidence rate decreased by over 50% in low-risk DCIS with RT (p < 0.001). CONCLUSIONS RT is associated with a lowered IBE incidence rate in DCIS patients, regardless of the assigned risk levels for patients. The significant reduction in the IBE incidence rate in low-risk DCIS patients also indicates the potential benefits for recommending RT to such a patient population in clinical practice.
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Affiliation(s)
- Libo Yang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Dongli Lu
- Department of Life Sciences, Imperial College London, London, UK
| | - Yutian Lai
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mengjia Shen
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Qiuxiao Yu
- Department of Pathology, Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Ting Lei
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Tianjie Pu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Bu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China. .,Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China. .,Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, China.
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20
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Moon HR, Ospina-Muñoz N, Noe-Kim V, Yang Y, Elzey BD, Konieczny SF, Han B. Subtype-specific characterization of breast cancer invasion using a microfluidic tumor platform. PLoS One 2020; 15:e0234012. [PMID: 32544183 PMCID: PMC7297326 DOI: 10.1371/journal.pone.0234012] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/15/2020] [Indexed: 12/21/2022] Open
Abstract
Understanding progression of breast cancers to invasive ductal carcinoma (IDC) can significantly improve breast cancer treatments. However, it is still difficult to identify genetic signatures and the role of tumor microenvironment to distinguish pathological stages of pre-invasive lesion and IDC. Presence of multiple subtypes of breast cancers makes the assessment more challenging. In this study, an in-vitro microfluidic assay was developed to quantitatively assess the subtype-specific invasion potential of breast cancers. The developed assay is a microfluidic platform in which a ductal structure of epithelial cancer cells is surrounded with a three-dimensional (3D) collagen matrix. In the developed platform, two triple negative cancer subtypes (MDA-MB-231 and SUM-159PT) invaded into the surrounding matrix but the luminal A subtype, MCF-7, did not. Among invasive subtypes, SUM-159PT cells showed significantly higher invasion and degradation of the surrounding matrix than MDA-MB-231. Interestingly, the cells cultured on the platform expressed higher levels of CD24 than in their conventional 2D cultures. This microfluidic platform may be a useful tool to characterize and predict invasive potential of breast cancer subtypes or patient-derived cells.
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Affiliation(s)
- Hye-ran Moon
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, United States of America
| | - Natalia Ospina-Muñoz
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, United States of America
- Cellular and Molecular Physiology Group, School of Medicine, Universidad Nacional de Colombia, Bogotá D.C, Colombia
| | - Victoria Noe-Kim
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, United States of America
| | - Yi Yang
- Department of Biological Science, Purdue University, West Lafayette, IN, United States of America
| | - Bennett D. Elzey
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States of America
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, United States of America
| | - Stephen F. Konieczny
- Department of Biological Science, Purdue University, West Lafayette, IN, United States of America
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, United States of America
| | - Bumsoo Han
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, United States of America
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, United States of America
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United States of America
- * E-mail:
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21
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Ductal Carcinoma In Situ of the Breast: Perspectives on Tumor Subtype and Treatment. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7251431. [PMID: 32596362 PMCID: PMC7275239 DOI: 10.1155/2020/7251431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 04/18/2020] [Indexed: 01/26/2023]
Abstract
Objective To evaluate ductal carcinoma in situ (DCIS) characteristics and the effect of different treatment strategies. Patients and Methods. Using data with known hormone receptor (HoR) and human epidermal growth factor receptor 2 (HER2) status obtained by the Surveillance, Epidemiology, and End Results (SEER) program from 2010-2014, the study was conducted to investigate tumor subtype-specific differences in various characteristics, overall survival (OS), and breast cancer-specific mortality (BCSM). Results A total of 3415 patients with DCIS were eligible. Compared with HoR+/HER- subgroup, patients with triple-negative (TN) and HoR-/HER+ were commonly higher in grade, larger in size, and tended to receive mastectomy (P < 0.05). The multivariate analysis revealed that patients with TN were more likely to have a poorer OS and show a higher breast cancer-specific mortality compared with the HoR+/HER- subgroup (P < 0.05). Multivariate analysis on the history of local treatment and surgery showed patients receiving breast-conserving surgery (BCS) plus radiotherapy (R) and BCS plus axillary lymph node dissection was likely to improve OS without affecting breast cancer-specific mortality (P < 0.05). Conclusion The results demonstrate that DCIS associated with TN subtype portends poor prognosis. Meanwhile, BCS plus R was a preferable option and resulted in survival rates better than those achieved with mastectomy, and SLNB should be considered as an appropriate assessment of axillary staging in patients with DCIS.
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22
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Xiao GQ, Golestani R, Pham H, Sherrod AE. Stratification of Atypical Intraepithelial Prostatic Lesions Based on Basal Cell and Architectural Patterns. Am J Clin Pathol 2020; 153:407-416. [PMID: 31781737 DOI: 10.1093/ajcp/aqz183] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES High-grade prostatic intraepithelial neoplasia (HPIN) and atypical cribriform lesion of the prostate are considered the precursors or associators of invasive prostate cancer (iPCa). Given loss of basal cells being the hallmark of iPCa, we hypothesized that a subset of these atypical intraepithelial lesions (AILs) with sparse basal cells can be classified as prostatic intraepithelial carcinoma (PIC) with frequent iPCa association and that different morphologic patterns of PIC are associated with specific Gleason (G) patterns and scores for iPCa. METHODS We stratified 153 foci of AILs from 110 patients based on the integrity of the basal cell layer and architectural patterns and their association with iPCa. RESULTS We demonstrated that AILs could be stratified into usual HPIN (intact basal cell layer and simple patterns) with low-risk of iPCa association and PIC (sparse basal cell layer) with high risk of iPCa association. Furthermore, PIC could be divided into low-grade (simple patterns and associated with G3 and G3/4 iPCa) and high-grade PIC (complex patterns and associated with G4 and G3/4/5 iPCa). CONCLUSIONS Such stratification is of great clinical significance and instrumental to clinical patient management. It not only increases the predictability of AILs for iPCa but also accommodates a clinical scenario for lesions with features of intraductal carcinoma when iPCa is not found, particularly in biopsies.
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Affiliation(s)
- Guang-Qian Xiao
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles
| | - Reza Golestani
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles
| | - Huy Pham
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles
| | - Andy E Sherrod
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles
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23
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Agahozo MC, van Bockstal MR, Groenendijk FH, van den Bosch TPP, Westenend PJ, van Deurzen CHM. Ductal carcinoma in situ of the breast: immune cell composition according to subtype. Mod Pathol 2020; 33:196-205. [PMID: 31375764 DOI: 10.1038/s41379-019-0331-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 07/03/2019] [Accepted: 07/03/2019] [Indexed: 11/09/2022]
Abstract
Ductal carcinoma in situ of the breast includes several subtypes with a divergent biological behavior. Data regarding the composition of ductal carcinoma in situ-associated immune cells and their potential role in progression is limited. We studied ductal carcinoma in situ-associated immune response by characterizing immune cell subsets according to ductal carcinoma in situ subtypes. Ductal carcinoma in situ-associated tumor infiltrating lymphocyte (TIL) density was evaluated based on hematoxylin and eosin (H&E)-stained sections from 473 patients. Cases were subtyped based on ER, PR, and HER2. Patients were categorized as TIL-high or low. Ductal carcinoma in situ-associated immune cells of TIL-high cases were immunostained on whole slides with CD4, CD8, CD20, CD68, FOXP3, and PD-L1 (SP142 and SP263). In total, 131/473 patients (28.0%) were considered as TIL-high. The percentage of TIL-high cases was significantly higher in HER2+ and triple-negative ductal carcinoma in situ (P < 0.0001). Overall, no statistical difference in immune cell composition according to subtypes was found. However, individual subtype comparison showed that ER+ HER2+ cases had a significantly higher proportion of CD8+ T cells compared with triple-negative cases (P = 0.047). In TIL-high cases, PD-L1-SP142 expression on tumor cells was associated with subtype (P = 0.037); the lowest number of positive cases was observed in the HER2+ subtype (independent of ER). However, in TIL-high ductal carcinoma in situ, PD-L1 expression by both clones was limited. In conclusion, high numbers of TILs are predominantly observed in HER+ and triple negative ductal carcinoma in situ. The ER+ HER2+ subtype seems to attract a higher proportion of CD8+ T cells compared with the triple negative subtype. Among TIL-high cases, the HER2+ subgroup had the lowest PD-L1-SP142 expression on tumor cells. This suggests a more pronounced antitumor immunity in HER2+ ductal carcinoma in situ, which could play a role in its biological behavior.
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Affiliation(s)
| | - Mieke R van Bockstal
- Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Floris H Groenendijk
- Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
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24
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Rosa M, Agosto-Arroyo E. Core needle biopsy of benign, borderline and in-situ problematic lesions of the breast: Diagnosis, differential diagnosis and immunohistochemistry. Ann Diagn Pathol 2019; 43:151407. [PMID: 31634810 DOI: 10.1016/j.anndiagpath.2019.151407] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 08/22/2019] [Accepted: 09/02/2019] [Indexed: 12/11/2022]
Abstract
Core needle biopsy (CNB) is the most common sampling technique for the histologic evaluation of breast abnormalities. Diagnosing benign proliferative, borderline and some in-situ lesions in CNB is challenging and subject to a significant degree of interobserver variability. In addition, due to the inherent limitations of CNB, "upgrading" to a more significant pathology at excision is an important consideration for some lesions. Pathologists carry a major responsibility in patient diagnosis, risk stratification and management. Familiarity with the histologic features and the clinical significance of these common and problematic lesions encountered in CNB is necessary for adequate treatment and patient follow-up. This review will focus on benign, atypical and in-situ epithelial proliferations, papillary lesions, radial sclerosing lesions, adenosis and cellular fibroepithelial lesions. Highlights of histologic features, useful strategies for accurate diagnosis, basic immunohistochemistry and management will be presented.
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Affiliation(s)
- Marilin Rosa
- Department of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, United States of America.
| | - Emmanuel Agosto-Arroyo
- Department of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, United States of America.
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25
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Dessources K, Sebastiao APM, Pareja F, Weigelt B, Reis-Filho JS. How Did We Get There? The Progression from Ductal Carcinoma In Situ to Invasive Ductal Carcinoma. CURRENT BREAST CANCER REPORTS 2019. [DOI: 10.1007/s12609-019-00318-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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26
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Solans BP, López-Díaz de Cerio A, Elizalde A, Pina LJ, Inogés S, Espinós J, Salgado E, Mejías LD, Trocóniz IF, Santisteban M. Assessing the impact of the addition of dendritic cell vaccination to neoadjuvant chemotherapy in breast cancer patients: A model-based characterization approach. Br J Clin Pharmacol 2019; 85:1670-1683. [PMID: 30933365 DOI: 10.1111/bcp.13947] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 03/08/2019] [Accepted: 03/27/2019] [Indexed: 12/27/2022] Open
Affiliation(s)
- Belén P Solans
- Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IdisNA), University of Navarra, Pamplona, Spain
| | - Ascensión López-Díaz de Cerio
- Navarra Institute for Health Research (IdisNA), University of Navarra, Pamplona, Spain.,Cell Therapy Area and Department of Immunology and Inmunotherapy, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Arlette Elizalde
- Department of Radiology, Breast Cancer Unit, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Luis Javier Pina
- Department of Radiology, Breast Cancer Unit, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Susana Inogés
- Navarra Institute for Health Research (IdisNA), University of Navarra, Pamplona, Spain.,Cell Therapy Area and Department of Immunology and Inmunotherapy, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Jaime Espinós
- Department of Medical Oncology, Breast Cancer Unit, Clínica, Universidad de Navarra, Pamplona, Navarra, Spain
| | - Esteban Salgado
- Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Luis Daniel Mejías
- Department of Pathology, Breast Cancer Unit, Clínica Universidad de Navarra, Pamplona, Navarra, Spain
| | - Iñaki F Trocóniz
- Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.,Navarra Institute for Health Research (IdisNA), University of Navarra, Pamplona, Spain
| | - Marta Santisteban
- Navarra Institute for Health Research (IdisNA), University of Navarra, Pamplona, Spain.,Department of Medical Oncology, Breast Cancer Unit, Clínica, Universidad de Navarra, Pamplona, Navarra, Spain
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27
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Balyimez A, Stephans KL, Abazeed ME, Mian OY. The landscape of early carcinogenesis revealed through the lens of integrative genomics, epigenomics, and transcriptomics. J Thorac Dis 2019; 11:2188-2191. [PMID: 31372248 PMCID: PMC6626785 DOI: 10.21037/jtd.2019.06.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 05/31/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Aysegul Balyimez
- Department of Translational Hematology and Oncology Research, Lerner Research Institute, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Kevin L. Stephans
- Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Mohamed E. Abazeed
- Department of Translational Hematology and Oncology Research, Lerner Research Institute, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Omar Y. Mian
- Department of Translational Hematology and Oncology Research, Lerner Research Institute, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
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28
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Prognostic role of immune infiltrates in breast ductal carcinoma in situ. Breast Cancer Res Treat 2019; 177:17-27. [PMID: 31134489 DOI: 10.1007/s10549-019-05272-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 05/06/2019] [Indexed: 01/13/2023]
Abstract
PURPOSE Ductal carcinoma in situ (DCIS) of the breast is often regarded as a non-obligate precursor to invasive breast carcinoma but current diagnostic tools are unable to accurately predict the invasive potential of DCIS. Infiltration of immune cells into the tumour and its microenvironment is often an early event at the site of tumourigenesis. These immune infiltrates may be potential predictive and/or prognostic biomarkers for DCIS. This review aims to discuss recent findings pertaining to the potential prognostic significance of immune infiltrates as well as their evaluation in DCIS. METHODS A literature search on PubMed was conducted up to 28th January 2019. Search terms used were "DCIS", "ductal carcinoma in situ", "immune", "immunology", "TIL", "TIL assessment", and "tumour-infiltrating lymphocyte". Search filters for "Most Recent" and "English" were applied. Information from published papers related to the research topic were synthesised and summarised for this review. RESULTS Studies have revealed that immune infiltrates play a role in the biology and microenvironment of DCIS, as well as treatment response. There is currently no consensus on the evaluation of TILs in DCIS for clinical application. CONCLUSIONS This review highlights the recent findings on the potential influence and prognostic value of immunological processes on DCIS progression, as well as the evaluation of TILs in DCIS. Further characterisation of the immune milieu of DCIS is recommended to better understand the immune response in DCIS progression and recurrence.
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29
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Koh VCY, Lim JCT, Thike AA, Cheok PY, Thu MMM, Li H, Tan VKM, Ong KW, Tan BKT, Ho GH, Thilagaratnam S, Wong JSL, Wong FY, Ellis IO, Tan PH. Behaviour and characteristics of low‐grade ductal carcinomain situof the breast: literature review and single‐centre retrospective series. Histopathology 2019; 74:970-987. [DOI: 10.1111/his.13837] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
| | | | - Aye Aye Thike
- Division of Pathology Singapore General Hospital Singapore
- Duke‐NUS Medical School Singapore
| | - Poh Yian Cheok
- Division of Pathology Singapore General Hospital Singapore
| | | | - Huihua Li
- Health Services Research Unit Singapore General Hospital Singapore
| | | | - Kong Wee Ong
- Division of Surgical Oncology National Cancer Centre Singapore Singapore
| | | | - Gay Hui Ho
- Division of Surgical Oncology National Cancer Centre Singapore Singapore
| | - Shyamala Thilagaratnam
- Regional Health and Community Outreach Division Singapore
- Saw Swee Hock School of Public Health Singapore
| | - Jill Su Lin Wong
- Division of Oncologic Imaging National Cancer Centre Singapore Singapore
| | - Fuh Yong Wong
- Division of Radiation Oncology National Cancer Centre Singapore Singapore
| | | | - Puay Hoon Tan
- Division of Pathology Singapore General Hospital Singapore
- Duke‐NUS Medical School Singapore
- Department of Anatomy Yong Loo Lin School of Medicine Singapore
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30
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Sowunmi A, Olatunji T, Ketiku K, Campbell O. Sociodemographic correlates and management of breast cancer in Radiotherapy Department, Lagos University Teaching Hospital: A 10-year review. JOURNAL OF CLINICAL SCIENCES 2019. [DOI: 10.4103/jcls.jcls_82_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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31
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Anti-proliferative effect of chitosan nanoparticles (extracted from crayfish Procambarus clarkii, Crustacea: Cambaridae) against MDA-MB-231 and SK-BR-3 human breast cancer cell lines. Int J Biol Macromol 2018; 126:478-487. [PMID: 30572045 DOI: 10.1016/j.ijbiomac.2018.12.151] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 12/05/2018] [Accepted: 12/16/2018] [Indexed: 12/17/2022]
Abstract
Actually, the most common cancer in women is the breast cancer which is the second most widespread cancer overall. In 2018, there were over two million new cases of women breast cancer. Particularly, we tried to extract chitosan from crayfish Procambarus clarkii, Crustacea: Cambaridae, by N-deacetylation of chitin. The chemical structure of chitosan was characterized by Fourier transform infrared (FT-IR) spectroscopy. Also DDA was calculated from FT-IR and ultraviolet spectrophotometry data. Chitosan nanoparticles were prepared using a ball-milling technique. The as-prepared chitosan nanoparticles were characterized by transmission electron microscopy, dynamic light scattering as well as zeta potential. The cytotoxicity of chitosan and its nanoparticles (50 and 100 μg/mL) against human breast cancer (SK BR3 and MDA-MB-231 cell lines) was evaluated. MTT assay asserts the significant inhibitory action of both chitosan and its nanoparticles on the proliferation of human breast cancer cells in vitro. Chitosan nanoparticles had more anti-proliferative effects on MDA-MB-231 and SK-BR-3 cell lines than its corresponding chitosan. Although, chitosan nanoparticles, that has higher DDA, had a higher cytotoxic activity against human breast cancer MDA-MB-231 and SK-BR-3 cell lines in vitro. Eventually, chitosan and its nanoparticles can be considered as a promising natural compounds in human breast cancer treatment.
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Shee K, Muller KE, Marotti J, Miller TW, Wells WA, Tsongalis GJ. Ductal Carcinoma in Situ Biomarkers in a Precision Medicine Era: Current and Future Molecular-Based Testing. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 189:956-965. [PMID: 30385093 DOI: 10.1016/j.ajpath.2018.08.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/09/2018] [Accepted: 08/30/2018] [Indexed: 12/18/2022]
Abstract
Historically, ductal carcinoma in situ (DCIS) of the breast has been managed aggressively with surgery and radiotherapy because of a risk of progression to invasive ductal carcinoma. However, this treatment paradigm has been challenged by overtreatment concerns and evidence that suggests that DCIS can be stratified according to risk of recurrence or risk of progression to invasive disease. Traditional methods of risk stratification include histologic grade and hormone receptor status. Recent technological advancements have enabled an era of precision medicine, where DCIS can be molecularly analyzed by tools, such as next-generation DNA and RNA sequencing, to identify molecular biomarkers for risk stratification. These findings have led to the development of tools such as the Oncotype DX Breast DCIS Score, a gene expression-based assay with the potential to prevent overtreatment in low-risk disease.
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Affiliation(s)
- Kevin Shee
- Department of Molecular & Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon
| | - Kristen E Muller
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Jonathan Marotti
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Todd W Miller
- Department of Molecular & Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon
| | - Wendy A Wells
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Gregory J Tsongalis
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire.
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Roguljic A, Spagnoli G, Juretic A, Sarcevic B, Banovic M, Beketic Oreskovic L. Possible predictive role of cancer/testis antigens in breast ductal carcinoma in situ. Oncol Lett 2018; 16:7245-7255. [PMID: 30546463 PMCID: PMC6256292 DOI: 10.3892/ol.2018.9544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 09/27/2018] [Indexed: 01/10/2023] Open
Abstract
Cancer/testis antigens (CTAs) are a large family of tumor-associated antigens expressed in human tumors of different histological origin, but not in normal tissues, with the exception of the testes and placenta. Numerous immunohistochemical studies have reported associations between CTA expression and a negative estrogen receptor (ER) status in breast tumors, and demonstrated that CTAs are frequently expressed in tumors with higher nuclear grade. The expression of CTAs has not been studied as extensively in ductal carcinoma in situ (DCIS) as it has been in invasive breast cancer. The present retrospective study included archived paraffin-embedded specimens from 83 patients diagnosed with DCIS in the period between January 2007 and December 2014. The follow-up time for local recurrence ranged between 1 and 8 years (mean, 5.02 years). Antigens from the melanoma-associated antigen gene (MAGE) family, namely multi-MAGE-A, MAGE-A1, MAGE-A10 and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen, were evaluated by immunostaining and their subcellular location was investigated. Presence of tumor-infiltrating lymphocytes (TILs) was evaluated on all sections, together with the histopathological variables of DCIS. Specific tested antigens exhibited associations with histopathological parameters for DCIS and all demonstrated statistically significant associations with nuclear staining, simultaneous cytoplasmic and nuclear staining, and local recurrence. Antigen MAGE-A10 demonstrated a significant association with higher expression of ER (P=0.005) and higher tumor nuclear grade (P=0.001), cytoplasmic staining (P=0.029) and antigen NY-ESO-1 with higher tumor size (P=0.001), expression of TILs (P=0.001) and R1 resection (P=0.001). A χ2 test revealed significant associations between simultaneous cytoplasmic and nuclear staining and local recurrence (P=0.005), central necrosis (P=0.016), and the expression of ER (P=0.003) and progesterone receptor (PR) (P=0.010). Additional analysis revealed an association between antigen MAGE-A10 and TILs (P=0.05). Additional analysis of TILs indicated that they were significantly associated with tumor grade (P=0.023), central necrosis (P<0.001), ER (P=0.003) and PR (P=0.029). Overall, CTAs from the MAGE family (MAGE-A1, multi-MAGE-A and MAGE-A10) and NY-ESO-1 associate with histopathological predictive variables of DCIS. The expression of antigens NY-ESO-1 and MAGE-A10 could serve an important role in the treatment of patients with negative histopathological predictive variables, but further analysis is required. Simultaneous cytoplasmic and nuclear protein expression of MAGE-A family and NY-ESO-1 CTAs may represent an independent marker for local recurrence. Taken together, the present data suggest that CTAs are not perfect indicators of invasiveness for DCIS, but could inform treatment strategies for patients when taken in combination with other histopathological predictive variables. However, this was a small study and further larger studies will be necessary to confirm the current findings.
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Affiliation(s)
- Ana Roguljic
- Department of Radiation and Medical Oncology, Sisters of Mercy University Hospital Center, University Hospital for Tumors, 10000 Zagreb, Croatia
| | - Gulio Spagnoli
- Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland
| | - Antonio Juretic
- Department of Oncology, Clinical Hospital Center Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia
| | - Bozena Sarcevic
- Department of Oncology-Pathology, University of Zagreb School of Medicine, Sisters of Mercy University Hospital Center, University Hospital for Tumors, 10000 Zagreb, Croatia
| | - Marija Banovic
- University of Zagreb School of Medicine, 10000 Zagreb, Croatia
| | - Lidija Beketic Oreskovic
- Department of Oncology, University of Zagreb School of Medicine, Sisters of Mercy University Hospital Center, University Hospital for Tumors, 10000 Zagreb, Croatia
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Shah S, Brock EJ, Jackson RM, Ji K, Boerner JL, Sloane BF, Mattingly RR. Downregulation of Rap1Gap: A Switch from DCIS to Invasive Breast Carcinoma via ERK/MAPK Activation. Neoplasia 2018; 20:951-963. [PMID: 30144784 PMCID: PMC6106701 DOI: 10.1016/j.neo.2018.07.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 07/06/2018] [Accepted: 07/12/2018] [Indexed: 01/13/2023] Open
Abstract
Diagnosis of breast ductal carcinoma in situ (DCIS) presents a challenge since we cannot yet distinguish those cases that would remain indolent and not require aggressive treatment from cases that may progress to invasive ductal cancer (IDC). The purpose of this study is to determine the role of Rap1Gap, a GTPase activating protein, in the progression from DCIS to IDC. Immunohistochemistry (IHC) analysis of samples from breast cancer patients shows an increase in Rap1Gap expression in DCIS compared to normal breast tissue and IDCs. In order to study the mechanisms of malignant progression, we employed an in vitro three-dimensional (3D) model that more accurately recapitulates both structural and functional cues of breast tissue. Immunoblotting results show that Rap1Gap levels in MCF10.Ca1D cells (a model of invasive carcinoma) are reduced compared to those in MCF10.DCIS (a model of DCIS). Retroviral silencing of Rap1Gap in MCF10.DCIS cells activated extracellular regulated kinase (ERK) mitogen-activated protein kinase (MAPK), induced extensive cytoskeletal reorganization and acquisition of mesenchymal phenotype, and enhanced invasion. Enforced reexpression of Rap1Gap in MCF10.DCIS-Rap1GapshRNA cells reduced Rap1 activity and reversed the mesenchymal phenotype. Similarly, introduction of dominant negative Rap1A mutant (Rap1A-N17) in DCIS-Rap1Gap shRNA cells caused a reversion to nonmalignant phenotype. Conversely, expression of constitutively active Rap1A mutant (Rap1A-V12) in noninvasive MCF10.DCIS cells led to phenotypic changes that were reminiscent of Rap1Gap knockdown. Thus, reduction of Rap1Gap in DCIS is a potential switch for progression to an invasive phenotype. The Graphical Abstract summarizes these findings.
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Affiliation(s)
- Seema Shah
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Ethan J Brock
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Ryan M Jackson
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Kyungmin Ji
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Julie L Boerner
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Bonnie F Sloane
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Raymond R Mattingly
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.
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Tumor-infiltrating lymphocytes and ductal carcinoma in situ of the breast: friends or foes? Mod Pathol 2018; 31:1012-1025. [PMID: 29463884 DOI: 10.1038/s41379-018-0030-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 01/05/2018] [Accepted: 01/07/2018] [Indexed: 12/11/2022]
Abstract
In the past three decades, the detection rate of ductal carcinoma in situ of the breast has dramatically increased due to breast screening programs. As a consequence, about 20% of all breast cancer cases are detected in this early in situ stage. Some ductal carcinoma in situ cases will progress to invasive breast cancer, while other cases are likely to have an indolent biological behavior. The presence of tumor-infiltrating lymphocytes is seen as a promising prognostic and predictive marker in invasive breast cancer, mainly in HER2-positive and triple-negative subtypes. Here, we summarize the current understanding regarding immune infiltrates in invasive breast cancer and highlight recent observations regarding the presence and potential clinical significance of such immune infiltrates in patients with ductal carcinoma in situ. The presence of tumor-infiltrating lymphocytes, their numbers, composition, and potential relationship with genomic status will be discussed. Finally, we propose that a combination of genetic and immune markers may better stratify ductal carcinoma in situ subtypes with respect to tumor evolution.
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Wu Q, Li J, Sun S, Zhu S, Chen C, Wu J, Liu Q, Wei W, Sun S. Breast carcinoma in situ: An observational study of tumor subtype, treatment and outcomes. Oncotarget 2018; 8:2361-2371. [PMID: 27926499 PMCID: PMC5356806 DOI: 10.18632/oncotarget.13785] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 11/23/2016] [Indexed: 11/25/2022] Open
Abstract
Background & Aims To evaluate the clinical presentation, treatment and outcome of patients with breast carcinoma in situ (BCIS) with special emphasis on the role of the tumor subtype and local treatment in these patients. Methods Using data obtained by the Surveillance, Epidemiology, and End Results (SEER) program from 2010-2013, a retrospective, population-based cohort study was conducted to investigate tumor subtype-specific differences in various characteristics, overall survival (OS) and breast cancer-specific mortality (BCSM). Results In all, 6867 patients with BCIS were eligible during the 2010-2013 study period. Compared with the hormone receptor (HoR)+/HER- subgroup, patients with triple negative (TN) breast cancer were more likely to have tumors that were higher in grade and larger in size; they were also more likely to have tumors with ductal and comedo histology and were less likely to have tumors with cribriform and papillary histology (each P < 0.05). During the follow-up period, patients with TN breast cancer had an OS of 97.0% compared with 98.6 % in the HoR+/HER- subgroup (P < 0.05). Furthermore, the BCSM rate was 1.0% for the TN group compared with 0.1% for the HoR+/HER- subgroup (P < 0.05). Multivariate analysis revealed that patients with TN MBC had a poorer OS and BCSM (P <0.05). Multivariate analysis of OS with respect to the local treatment history showed that patients who received breast-conserving surgery (BCS) combined with radiotherapy (R) were more likely to have an improved OS (P < 0.05). Moreover, the results demonstrated that patients who underwent SLNB were more likely to have a lower BCSM (P < 0.05). Conclusions The results demonstrate that BCIS appears to alter the prognosis associated with the TN subtype. Meanwhile, BCS plus R was a preferable option and resulted in survival rates that were better than those achieved with mastectomy; thus, SLNB should be considered as an appropriate assessment of axillary staging in patients with BCIS.
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Affiliation(s)
- Qi Wu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Juanjuan Li
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Si Sun
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Shan Zhu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Chuang Chen
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Juan Wu
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Qian Liu
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Wen Wei
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
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Aleskandarany MA, Vandenberghe ME, Marchiò C, Ellis IO, Sapino A, Rakha EA. Tumour Heterogeneity of Breast Cancer: From Morphology to Personalised Medicine. Pathobiology 2018; 85:23-34. [DOI: 10.1159/000477851] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 05/30/2017] [Indexed: 12/11/2022] Open
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Arachidonic Acid Metabolite as a Novel Therapeutic Target in Breast Cancer Metastasis. Int J Mol Sci 2017; 18:ijms18122661. [PMID: 29292756 PMCID: PMC5751263 DOI: 10.3390/ijms18122661] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 12/02/2017] [Accepted: 12/06/2017] [Indexed: 12/14/2022] Open
Abstract
Metastatic breast cancer (BC) (also referred to as stage IV) spreads beyond the breast to the bones, lungs, liver, or brain and is a major contributor to the deaths of cancer patients. Interestingly, metastasis is a result of stroma-coordinated hallmarks such as invasion and migration of the tumor cells from the primary niche, regrowth of the invading tumor cells in the distant organs, proliferation, vascularization, and immune suppression. Targeted therapies, when used as monotherapies or combination therapies, have shown limited success in decreasing the established metastatic growth and improving survival. Thus, novel therapeutic targets are warranted to improve the metastasis outcomes. We have been actively investigating the cytochrome P450 4 (CYP4) family of enzymes that can biosynthesize 20-hydroxyeicosatetraenoic acid (20-HETE), an important signaling eicosanoid involved in the regulation of vascular tone and angiogenesis. We have shown that 20-HETE can activate several intracellular protein kinases, pro-inflammatory mediators, and chemokines in cancer. This review article is focused on understanding the role of the arachidonic acid metabolic pathway in BC metastasis with an emphasis on 20-HETE as a novel therapeutic target to decrease BC metastasis. We have discussed all the significant investigational mechanisms and put forward studies showing how 20-HETE can promote angiogenesis and metastasis, and how its inhibition could affect the metastatic niches. Potential adjuvant therapies targeting the tumor microenvironment showing anti-tumor properties against BC and its lung metastasis are discussed at the end. This review will highlight the importance of exploring tumor-inherent and stromal-inherent metabolic pathways in the development of novel therapeutics for treating BC metastasis.
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Gorringe KL, Fox SB. Ductal Carcinoma In Situ Biology, Biomarkers, and Diagnosis. Front Oncol 2017; 7:248. [PMID: 29109942 PMCID: PMC5660056 DOI: 10.3389/fonc.2017.00248] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 10/02/2017] [Indexed: 12/21/2022] Open
Abstract
Ductal carcinoma in situ (DCIS) is an often-diagnosed breast disease and a known, non-obligate, precursor to invasive breast carcinoma. In this review, we explore the clinical and pathological features of DCIS, fundamental elements of DCIS biology including gene expression and genetic events, the relationship of DCIS with recurrence and invasive breast cancer, and the interaction of DCIS with the microenvironment. We also survey how these various elements are being used to solve the clinical conundrum of how to optimally treat a disease that has potential to progress, and yet is also likely over-treated in a significant proportion of cases.
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Affiliation(s)
- Kylie L. Gorringe
- Cancer Genomics Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
| | - Stephen B. Fox
- The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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Current Approaches to Diagnosis and Treatment of Ductal Carcinoma In Situ and Future Directions. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 151:33-80. [PMID: 29096897 DOI: 10.1016/bs.pmbts.2017.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The presentation and treatment of ductal carcinoma in situ (DCIS) has changed substantially over the years. While previously an incidental pathologic finding in more advanced, palpable tumors, the institution of screening mammography has repositioned this disease entity as one largely diagnosed as a non-palpable lesion, often prior to any invasive disease. As DCIS is a precursor to invasive carcinoma, evolution in the approach to treatment has followed in the footsteps of that for invasive disease, including breast conservation therapy, adjuvant radiation, and use of antihormonal therapy. Survival outcomes for DCIS are very high and more recent literature has investigated tailoring therapeutic approaches to avoid overtreatment. Two important areas of ongoing clinical debate concerning overtreatment include use of preoperative MRI and the role of adjuvant radiation. The heterogeneity of the disease makes it difficult to differentiate lesions that would benefit from more aggressive treatment from those in which overtreatment could be avoided. Clinical characteristics, such as histologic appearance, age at diagnosis, and margin status at tumor excision have been established as moderate predictors of disease recurrence, but none has provided strong enough evidence as to guide consensus decisions on adjuvant therapy. Continuing research seeks to define the genetic and molecular characteristics that can predict disease course and serve as the potential targets for novel therapeutic agents. While several markers have shown promise in differentiating tumor aggressiveness, there is still much to be discovered about the precise mechanisms of disease progression and how this can be applied clinically to optimize treatment.
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Sagara Y, Julia W, Golshan M, Toi M. Paradigm Shift toward Reducing Overtreatment of Ductal Carcinoma In Situ of Breast. Front Oncol 2017; 7:192. [PMID: 28894698 PMCID: PMC5581351 DOI: 10.3389/fonc.2017.00192] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 08/11/2017] [Indexed: 12/27/2022] Open
Abstract
The prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially after the introduction of breast cancer screening programs, although the clinical effects of early DCIS detection and treatment remain unclear. The standard treatment for DCIS has involved local breast-conserving surgery (BCS) followed by radiotherapy (RT) or total mastectomy with/without endocrine therapy, and the choice of local treatment is not usually based on clinicopathologic or biological factors. However, we have investigated the effectiveness of local treatment using breast surgery and RT using Surveillance, Epidemiology, and End Results data, and found that the effectiveness of breast surgery was modified by the nuclear grade. Furthermore, breast cancer-specific survival was identical between patients with low-grade DCIS who did and did not undergo surgery. Moreover, we found that RT after BCS for DCIS was only associated with a survival benefit among patients with risk factors for local recurrence, such as nuclear grade, age, and tumor size. Ongoing clinical trials and translational research have attempted to develop a treatment strategy that prevents the overdiagnosis and overtreatment of low-risk DCIS, as well as a biology-based treatment strategy for using targeted therapy. Therefore, to develop a tailored treatment strategy for DCIS, we need to identify molecular and biological classifications based on the results from translational research, national databases, and clinical trials.
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Affiliation(s)
- Yasuaki Sagara
- Breast Cancer Unit, Kyoto University Hospital Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Breast Surgical Oncology, Hakuaikai Social Medical Cooperation, Kagoshima, Japan.,Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Wong Julia
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Mehra Golshan
- Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States
| | - Masakazu Toi
- Breast Cancer Unit, Kyoto University Hospital Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Doebar SC, Sieuwerts AM, de Weerd V, Stoop H, Martens JW, van Deurzen CH. Gene Expression Differences between Ductal Carcinoma in Situ with and without Progression to Invasive Breast Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2017. [DOI: 10.1016/j.ajpath.2017.03.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Carter EP, Gopsill JA, Gomm JJ, Jones JL, Grose RP. A 3D in vitro model of the human breast duct: a method to unravel myoepithelial-luminal interactions in the progression of breast cancer. Breast Cancer Res 2017; 19:50. [PMID: 28427436 PMCID: PMC5399380 DOI: 10.1186/s13058-017-0843-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 04/11/2017] [Indexed: 11/10/2022] Open
Abstract
Background 3D modelling fulfils a critical role in research, allowing for complex cell behaviour and interactions to be studied in physiomimetic conditions. With tissue banks becoming established for a number of cancers, researchers now have access to primary patient cells, providing the perfect building blocks to recreate and interrogate intricate cellular systems in the laboratory. The ducts of the human breast are composed of an inner layer of luminal cells supported by an outer layer of myoepithelial cells. In early-stage ductal carcinoma in situ, cancerous luminal cells are confined to the ductal space by an intact myoepithelial layer. Understanding the relationship between myoepithelial and luminal cells in the development of cancer is critical for the development of new therapies and prognostic markers. This requires the generation of new models that allows for the manipulation of these two cell types in a physiological setting. Methods Using access to the Breast Cancer Now Tissue Bank, we isolated pure populations of myoepithelial and luminal cells from human reduction mammoplasty specimens and placed them into 2D culture. These cells were infected with lentiviral particles encoding either fluorescent proteins, to facilitate cell tracking, or an inducible human epidermal growth factor receptor 2 (HER2) expression construct. Myoepithelial and luminal cells were then recombined in collagen gels, and the resulting cellular structures were analysed by confocal microscopy. Results Myoepithelial and luminal cells isolated from reduction mammoplasty specimens can be grown separately in 2D culture and retain their differentiated state. When recombined in collagen gels, these cells reform into physiologically reflective bilayer structures. Inducible expression of HER2 in the luminal compartment, once the bilayer has formed, leads to robust luminal filling, recapitulating ductal carcinoma in situ, and can be blocked with anti-HER2 therapies. Conclusions This model allows for the interaction between myoepithelial and luminal cells to be investigated in an in-vitro environment and paves the way to study early events in breast cancer development with the potential to act as a powerful drug discovery platform. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0843-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Edward P Carter
- Centre for Tumour Biology, Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK.
| | - James A Gopsill
- Department of Mechanical Engineering, University of Bristol, Bristol, BS8 1TR, UK
| | - Jennifer J Gomm
- Centre for Tumour Biology, Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - J Louise Jones
- Centre for Tumour Biology, Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Richard P Grose
- Centre for Tumour Biology, Barts Cancer Institute - a Cancer Research UK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK.
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Sarper M, Allen MD, Gomm J, Haywood L, Decock J, Thirkettle S, Ustaoglu A, Sarker SJ, Marshall J, Edwards DR, Jones JL. Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function. Breast Cancer Res 2017; 19:33. [PMID: 28330493 PMCID: PMC5363009 DOI: 10.1186/s13058-017-0822-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 03/02/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Normal myoepithelial cells (MECs) play an important tumour-suppressor role in the breast but display an altered phenotype in ductal carcinoma in situ (DCIS), gaining tumour-promoter functions. Matrix metalloproteinase-8 (MMP-8) is expressed by normal MECs but is lost in DCIS. This study investigated the function of MMP-8 in MECs and the impact of its loss in DCIS. METHODS Primary normal and DCIS-associated MECs, and normal (N-1089) and DCIS-modified myoepithelial (β6-1089) cell lines, were used to assess MMP-8 expression and function. β6-1089 lacking MMP-8 were transfected with MMP-8 WT and catalytically inactive MMP-8 EA, and MMP-8 in N-1089 MEC was knocked down with siRNA. The effect on adhesion and migration to extracellular matrix (ECM), localisation of α6β4 integrin to hemidesmosomes (HD), TGF-β signalling and gelatinase activity was measured. The effect of altering MEC MMP-8 expression on tumour cell invasion was investigated in 2D and 3D organotypic models. RESULTS Assessment of primary cells and MEC lines confirmed expression of MMP-8 in normal MEC and its loss in DCIS-MEC. Over-expression of MMP-8 WT but not MMP-8 EA in β6-1089 cells increased adhesion to ECM proteins and reduced migration. Conversely, knock-down of MMP-8 in N-1089 reduced adhesion and increased migration. Expression of MMP-8 WT in β6-1089 led to greater localisation of α6β4 to HD and reduced retraction fibre formation, this being reversed by MMP-8 knock-down in N-1089. Over-expression of MMP-8 WT reduced TGF-β signalling and gelatinolytic activity. MMP-8 knock-down enhanced TGF-β signalling and gelatinolytic activity, which was reversed by blocking MMP-9 by knock-down or an inhibitor. MMP-8 WT but not MMP-8 EA over-expression in β6-1089 reduced breast cancer cell invasion in 2D and 3D invasion assays, while MMP-8 knock-down in N-1089 enhanced cancer cell invasion. Staining of breast cancer cases for MMP-8 revealed a statistically significant loss of MMP-8 expression in DCIS with invasion versus pure DCIS (p = 0.001). CONCLUSIONS These data indicate MMP-8 is a vital component of the myoepithelial tumour-suppressor function. It restores MEC interaction with the matrix, opposes TGF-β signalling and MMP-9 proteolysis, which contributes to inhibition of tumour cell invasion. Assessment of MMP-8 expression may help to determine risk of DCIS progression.
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Affiliation(s)
- Muge Sarper
- Translational Cancer Discovery Team, CRUK Cancer Therapeutics Unit, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK
| | - Michael D Allen
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
| | - Jenny Gomm
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Linda Haywood
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Julie Decock
- Cancer Research Centre, Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar
| | - Sally Thirkettle
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Ahsen Ustaoglu
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Shah-Jalal Sarker
- Centre for Experimental Cancer Medicine, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - John Marshall
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Dylan R Edwards
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
| | - J Louise Jones
- Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
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Agosto-Arroyo E, Isayeva T, Wei S, Almeida JS, Harada S. Differential Gene Expression in Ductal Carcinoma In Situ of the Breast Based on ERBB2 Status. Cancer Control 2017; 24:102-110. [PMID: 28178722 DOI: 10.1177/107327481702400117] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The molecular signature of ductal carcinoma in situ (DCIS) in the breast is not well understood. Erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly known as HER2/neu]) positivity in DCIS is predictive of coexistent early invasive breast carcinoma. The aim of this study is to identify the gene-expression signature profiles of estrogen receptor (ER)/progesterone receptor (PR)-positive, ERBB2, and triple-negative subtypes of DCIS. METHODS Based on ER, PR, and ERBB2 status, a total of 18 high nuclear grade DCIS cases with no evidence of invasive breast carcinoma were selected along with 6 non-neoplastic controls. The 3 study groups were defined as ER/PR-positive, ERBB2, and triple-negative subtypes. RESULTS A total of 49 genes were differentially expressed in the ERBB2 subtype compared with the ER/PR-positive and triple-negative groups. PROM1 was overexpressed in the ERBB2 subtype compared with ER/PR-positive and triple-negative subtypes. Other genes differentially expressed included TAOK1, AREG, AGR3, PEG10, and MMP9. CONCLUSIONS Our study identified unique gene signatures in ERBB2-positive DCIS, which may be associated with the development of invasive breast carcinoma. The results may enhance our understanding of the progression of breast cancer and become the basis for developing new predictive biomarkers and therapeutic targets for DCIS.
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Affiliation(s)
| | - Tatyana Isayeva
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Shi Wei
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Jonas S Almeida
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Shuko Harada
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL.
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Diaz-Vera J, Palmer S, Hernandez-Fernaud JR, Dornier E, Mitchell LE, Macpherson I, Edwards J, Zanivan S, Norman JC. A proteomic approach to identify endosomal cargoes controlling cancer invasiveness. J Cell Sci 2017; 130:697-711. [PMID: 28062852 PMCID: PMC5339883 DOI: 10.1242/jcs.190835] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 12/15/2016] [Indexed: 12/17/2022] Open
Abstract
We have previously shown that Rab17, a small GTPase associated with epithelial polarity, is specifically suppressed by ERK2 (also known as MAPK1) signalling to promote an invasive phenotype. However, the mechanisms through which Rab17 loss permits invasiveness, and the endosomal cargoes that are responsible for mediating this, are unknown. Using quantitative mass spectrometry-based proteomics, we have found that knockdown of Rab17 leads to a highly selective reduction in the cellular levels of a v-SNARE (Vamp8). Moreover, proteomics and immunofluorescence indicate that Vamp8 is associated with Rab17 at late endosomes. Reduced levels of Vamp8 promote transition between ductal carcinoma in situ (DCIS) and a more invasive phenotype. We developed an unbiased proteomic approach to elucidate the complement of receptors that redistributes between endosomes and the plasma membrane, and have pin-pointed neuropilin-2 (NRP2) as a key pro-invasive cargo of Rab17- and Vamp8-regulated trafficking. Indeed, reduced Rab17 or Vamp8 levels lead to increased mobilisation of NRP2-containing late endosomes and upregulated cell surface expression of NRP2. Finally, we show that NRP2 is required for the basement membrane disruption that accompanies the transition between DCIS and a more invasive phenotype.
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Affiliation(s)
- Jesica Diaz-Vera
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
| | - Sarah Palmer
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
| | | | - Emmanuel Dornier
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
| | - Louise E Mitchell
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
| | - Iain Macpherson
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Joanne Edwards
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Sara Zanivan
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Jim C Norman
- Beatson Institute for Cancer Research, Garscube Estate, Glasgow G61 1BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
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Coutinho-Camillo CM, Lourenço SV, Puga RD, Damascena AS, Teshima THN, Kowalski LP, Soares FA. Profile of apoptotic proteins in oral squamous cell carcinoma: A cluster analysis of 171 cases. ACTA ACUST UNITED AC 2017. [DOI: 10.1186/s41241-016-0008-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Abstract
BACKGROUND A subset of patients with ductal carcinoma in situ (DCIS) experience recurrence or progression to invasive cancer. Current clinical practice is not reliably guided by DCIS recurrence prediction, although recurrence risk for invasive breast cancer can now be assessed. We analyzed a panel of biomarkers (estrogen receptor, Her2, Ki67, p53, cyclin D1, COX-2, caveolin-1, survivin, and PPAR-γ) and DCIS histologic and clinical features to determine associations with DCIS recurrence. MATERIALS AND METHODS Seventy DCIS cases diagnosed between 1995 and 2010 were divided into 2 groups: 52 had DCIS without known recurrence after excision and 18 had DCIS with subsequent recurrence after excision as DCIS or invasive carcinoma in the ipsilateral or contralateral breast. Tissue microarrays were prepared, immunohistochemistry performed, and expression of the biomarkers scored semiquantitatively. Variables analyzed included age, tumor size, margin status, DCIS grade, necrosis, histologic type, and immunohistochemistry scores. Differences between groups were evaluated using t tests for continuous variables and Fisher exact tests for categorical variables. RESULTS Intraductal necrosis was associated with increased recurrence risk: 46% of nonrecurrent cases showed necrosis compared with 83% of those who recurred (P=0.007). Her2 (human epidermal growth factor receptor 2) and Ki67 expression distributions were significantly different between nonrecurrent and recurrent cases. Her2 was overexpressed in 14% of nonrecurrent cases compared with 50% in the recurrent cases (P=0.03). A total of 87% of nonrecurrent cases had low Ki67 staining (0% to 10%) compared with 50% among the recurrent cases (P=0.002). CONCLUSION Our results suggest that Her2 and Ki67 immunohistochemistry and the presence of intraductal necrosis aid in DCIS risk stratification.
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Wilkinson JB, Shah C, Amin M, Nadeau L, Shaitelman SF, Chen PY, Grills IS, Martinez AA, Mitchell CK, Wallace MF, Vicini FA. Outcomes According to Breast Cancer Subtype in Patients Treated With Accelerated Partial Breast Irradiation. Clin Breast Cancer 2016; 17:55-60. [PMID: 27666436 DOI: 10.1016/j.clbc.2016.07.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 07/03/2016] [Accepted: 07/20/2016] [Indexed: 11/25/2022]
Abstract
BACKGROUND The purpose of the study was to determine outcomes for patients treated with accelerated partial breast irradiation (APBI) on the basis of breast cancer subtype (BCST). PATIENTS AND METHODS Our single-institution, institutional review board-approved APBI database was queried for patients who had complete testing results for the estrogen (ER), progesterone (PR), and HER2/neu receptors to determine outcomes for each BCST. Women were assigned as luminal A (LA), luminal B (LB), HER2, and basal BCST using their ER, PR, and HER2/neu receptor status. Degree of ER expression supplemented the receptor-based luminal BCST assignment. Two hundred seventy-eight patients had results for all 3 receptors (LA = 164 [59%], LB = 81 [29%], HER2 = 5 [2%], basal = 28 [10%]), which were submitted for analysis (ipsilateral breast tumor recurrence [IBTR], regional nodal failure, distant metastasis [DM], disease-free survival [DFS], cause-specific survival [CSS], and overall survival [OS]). RESULTS Median follow-up was 5.4 years (range, 0.1-12.4 years). Basal and HER2 subtype patients had higher histologic grades (Grade 3 = 75% vs. 10% LA/LB; P < .001), larger tumors (13.0 mm basal vs. 10.7 mm LA/LB; P = .059), and were more likely to receive chemotherapy (68% vs. 15% LA/LB; P < .001). Margin and nodal status were similar among BCSTs. At 5 years, IBTR rates were similar (1.8%, 2.9%, 0%, and 4.8%) for LA, LB, HER2, and basal subtypes, respectively (P = .62). DM was only seen in LA (2.9%) and LB (1.3%) (P = .83). DFS (95%-100%), CSS (97%-100%), and OS (80%-100%) were not statistically different (P = .97, .87, .46, respectively). CONCLUSION Five-year local control rates after breast-conserving surgery, APBI, and appropriate systemic therapy are excellent for luminal, HER2, and basal phenotypes of early-stage breast cancer; however, further study of receptor subtype effect on risk stratification in early-stage breast cancer is needed.
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Affiliation(s)
- J Ben Wilkinson
- Department of Radiation Oncology, Willis-Knighton Health System, Louisiana State University Health Sciences Center, Shreveport, LA.
| | - Chirag Shah
- Department of Radiation Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, Royal Oak, MI
| | - Mitual Amin
- Department of Pathology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, Royal Oak, MI
| | - Laura Nadeau
- Department of Medical Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, Royal Oak, MI
| | - Simona F Shaitelman
- Department of Radiation Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Peter Y Chen
- Department of Radiation Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, Royal Oak, MI
| | - Inga S Grills
- Department of Radiation Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, Royal Oak, MI
| | - Alvaro A Martinez
- Department of Radiation Oncology, Michigan Healthcare Professionals, 21st Century Oncology, Farmington Hills, MI
| | - Christina K Mitchell
- Department of Radiation Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, Royal Oak, MI
| | - Michelle F Wallace
- Department of Radiation Oncology, Beaumont Cancer Institute, Oakland University William Beaumont School of Medicine, Royal Oak, MI
| | - Frank A Vicini
- Department of Radiation Oncology, Michigan Healthcare Professionals, 21st Century Oncology, Farmington Hills, MI
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Rossetti S, Bshara W, Reiners JA, Corlazzoli F, Miller A, Sacchi N. Harnessing 3D models of mammary epithelial morphogenesis: An off the beaten path approach to identify candidate biomarkers of early stage breast cancer. Cancer Lett 2016; 380:375-383. [PMID: 27422542 DOI: 10.1016/j.canlet.2016.07.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 07/03/2016] [Accepted: 07/04/2016] [Indexed: 12/11/2022]
Abstract
Regardless of the etiological factor, an aberrant morphology is the common hallmark of ductal carcinoma in situ (DCIS), which is a highly heterogeneous disease. To test if critical core morphogenetic mechanisms are compromised by different mutations, we performed proteomics analysis of five mammary epithelial HME1 mutant lines that develop a DCIS-like morphology in three dimensional (3D) culture. Here we show first, that all HME1 mutant lines share a common protein signature highlighting an inverse deregulation of two annexins, ANXA2 and ANXA8. Either ANXA2 downregulation or ANXA8 upregulation in the HME1 cell context are per se sufficient to confer a 3D DCIS-like morphology. Seemingly, different mutations impinged on a common mechanism that differentially regulates the two annexins. Second, we show that ANXA8 expression is significantly higher in DCIS tissue samples versus normal breast tissue and atypical ductal hyperplasia (ADH). Apparently, ANXA8 expression is significantly more upregulated in ER-negative versus ER-positive cases, and significantly correlates with tumor stage, grade and positive lymph node. Based on our study, 3D mammary morphogenesis models can be an alternate/complementary strategy for unraveling new DCIS mechanisms and biomarkers.
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Affiliation(s)
- Stefano Rossetti
- Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Wiam Bshara
- Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Johanna A Reiners
- Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | | | - Austin Miller
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Nicoletta Sacchi
- Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
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