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1
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Downs E, Gulbahce HE. "Lobular lesions of the breast: From the classic to the variants". Semin Diagn Pathol 2024; 41:258-271. [PMID: 39510943 DOI: 10.1053/j.semdp.2024.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 10/03/2024] [Indexed: 11/15/2024]
Abstract
The aim of this review is to provide the surgical pathologist an overview of lobular lesions, from in situ to invasive carcinoma and the variants, by discussing the epidemiology, clinical characteristics, morphology, immunohistochemistry, known molecular data as well as the treatment recommendations. The recognition of histologic variants of both in situ and invasive lobular carcinoma has expanded the differential diagnosis. Awareness of these different entities is important as treatment recommendations continue to evolve.
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Affiliation(s)
- Erinn Downs
- Mayo Clinic Arizona Scottsdale, AZ, United States.
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2
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Clark AB, Conzen SD. Glucocorticoid receptor-mediated oncogenic activity is dependent on breast cancer subtype. J Steroid Biochem Mol Biol 2024; 243:106518. [PMID: 38734115 DOI: 10.1016/j.jsbmb.2024.106518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/23/2024] [Accepted: 04/08/2024] [Indexed: 05/13/2024]
Abstract
Breast cancer incidence has been steadily rising and is the leading cause of cancer death in women due to its high metastatic potential. Individual breast cancer subtypes are classified by both cell type of origin and receptor expression, namely estrogen, progesterone and human epidermal growth factor receptors (ER, PR and HER2). Recently, the importance and context-dependent role of glucocorticoid receptor (GR) expression in the natural history and prognosis of breast cancer subtypes have been uncovered. In ER-positive breast cancer, GR expression is associated with a better prognosis as a result of ER-GR crosstalk. GR appears to modulate ER-mediated gene expression resulting in decreased tumor cell proliferation and a more indolent cancer phenotype. In ER-negative breast cancer, including GR-positive triple-negative breast cancer (TNBC), GR expression enhances migration, chemotherapy resistance and cell survival. In invasive lobular carcinoma, GR function is relatively understudied, and more work is required to determine whether lobular subtypes behave similarly to their invasive ductal carcinoma counterparts. Importantly, understanding GR signaling in individual breast cancer subtypes has potential clinical implications because of the recent development of highly selective GR non-steroidal ligands, which represent a therapeutic approach for modulating GR activity systemically.
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Affiliation(s)
- Abigail B Clark
- Depatment of Internal Medicine, Division of Hematology and Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Suzanne D Conzen
- Depatment of Internal Medicine, Division of Hematology and Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
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3
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Guan Y, Huang ST, Yu BB. Nomograms to predict the long-term prognosis for non-metastatic invasive lobular breast carcinoma: a population-based study. Sci Rep 2024; 14:19477. [PMID: 39174612 PMCID: PMC11341842 DOI: 10.1038/s41598-024-68931-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 07/30/2024] [Indexed: 08/24/2024] Open
Abstract
Invasive lobular breast carcinoma (ILC) is one potential subset that "clinicopathologic features" can conflict with "long-term outcome" and the optimal management strategy is unknown in such discordant situations. The present study aims to predict the long-term, overall survival (OS) and cancer-specific survival (CSS) of ILC. The clinical information of patients with non-metastatic ILC was retrieved from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2020. A total of 31451 patients were enrolled and divided into the training cohort (n=22,017) and validation cohort (n=9434). The last follow-up was December, 31, 2020 and the median follow-up period was 99 months (1-203). Age, marriage, estrogen (ER) status, progesterone (PR) status, grade, tumor size, lymph node ratio (LNR) and combined summary (CS) stage were prognostic factors for both OS and CSS of ILC, whereas chemotherapy and radiation were independent protect factors for OS. The nomograms exhibited satisfactory discriminative ability. For the training and validation cohorts, the C-index of the OS nomogram was 0.765 (95% CI 0.762-0.768) and 0.757 (95% CI 0.747-0.767), and the C-index of the CSS nomogram were 0.812 (95% CI 0.804-0.820) and 0.813 (95% CI 0.799-0.827), respectively. Additionally, decision curve analysis (DCA) demonstrated that the nomograms had superior predictive performance than traditional American Joint Committee on Cancer (AJCC) TNM stage. The novel nomograms to predict long-term prognosis based on LNR are reliable tools to predict survival, which may assist clinicians in identifying high-risk patients and devising individual treatments for patients with ILC. Our findings should aid public health prevention strategies to reduce cancer burden. We provide two R/Shiny apps ( https://ilc-survival2024.shinyapps.io/osnomogram/ ; https://ilc-survival2024.shinyapps.io/cssnomogram/ ) to visualize findings.
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Affiliation(s)
- Ying Guan
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, No 71, Hedi Road, Nanning, 530021, Guangxi, People's Republic of China.
| | - Shi-Ting Huang
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, No 71, Hedi Road, Nanning, 530021, Guangxi, People's Republic of China
| | - Bin-Bin Yu
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, No 71, Hedi Road, Nanning, 530021, Guangxi, People's Republic of China
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4
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Flaherty RL, Sflomos G, Brisken C. Is There a Special Role for Ovarian Hormones in the Pathogenesis of Lobular Carcinoma? Endocrinology 2024; 165:bqae031. [PMID: 38551031 PMCID: PMC10988861 DOI: 10.1210/endocr/bqae031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Indexed: 04/04/2024]
Abstract
Lobular carcinoma represent the most common special histological subtype of breast cancer, with the majority classed as hormone receptor positive. Rates of invasive lobular carcinoma in postmenopausal women have been seen to increase globally, while other hormone receptor-positive breast cancers proportionally have not followed the same trend. This has been linked to exposure to exogenous ovarian hormones such as hormone replacement therapy. Reproductive factors resulting in increased lifetime exposure to endogenous ovarian hormones have also been linked to an increased risk of lobular breast cancer, and taken together, these data make a case for the role of ovarian hormones in the genesis and progression of the disease. In this review, we summarize current understanding of the epidemiological associations between ovarian hormones and lobular breast cancer and highlight mechanistic links that may underpin the etiology and biology.
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Affiliation(s)
- Renée L Flaherty
- Division of Breast Cancer Research, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
| | - George Sflomos
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Cathrin Brisken
- Division of Breast Cancer Research, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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5
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Öztekin S, Hooning MJ, van Deurzen CHM, Dietvorst AMHP, Drooger JC, Kitzen JJEM, Martens JWM, van der Padt-Pruijsten A, Vastbinder MB, Zuetenhorst H, Heemskerk-Gerritsen BAM, Jager A. The effect of (neo)adjuvant chemotherapy on long-term survival outcomes in patients with invasive lobular breast cancer treated with endocrine therapy: A retrospective cohort study. Cancer 2024; 130:927-935. [PMID: 37985357 DOI: 10.1002/cncr.35125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/23/2023] [Accepted: 10/26/2023] [Indexed: 11/22/2023]
Abstract
BACKGROUND Despite histological and molecular differences between invasive lobular carcinoma (ILC) and invasive carcinoma of no special type, according to national treatment guidelines no distinction is made regarding the use of (neo)adjuvant chemotherapy. Studies on the long-term outcome of chemotherapy in patients with ILC are scarce and show inconclusive results. METHODS All patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative ILC with an indication for chemotherapy treated with adjuvant endocrine therapy were selected from the Erasmus Medical Center Breast Cancer database. Cox proportional hazards models were used to estimate the effect of chemotherapy on recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). RESULTS A total of 520 patients were selected, of whom 379 were treated with chemotherapy and 141 were not. Patients in the chemotherapy group were younger (51 vs. 61 years old; p < .001), had a higher T status (T3+, 33% vs. 14%; p < .001), and more often had lymph node involvement (80% vs. 49%; p < .001) in comparison to the no-chemotherapy group. After adjusting for confounders, chemotherapy treatment was not associated with better RFS (hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.63-2.31), BCSS (HR, 1.24; 95% CI, 0.60-2.58), or OS (HR, 0.97; 95% CI, 0.56-1.66). This was also reflected by adjusted Cox survival curves in the chemotherapy versus no-chemotherapy group for RFS (75% vs. 79%), BCSS (80% vs. 84%), and OS (72% vs. 71%). CONCLUSIONS Chemotherapy is not associated with improved RFS, BCSS, or OS for patients with ER+/HER2- ILC treated with adjuvant endocrine therapy and with an indication for chemotherapy.
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Affiliation(s)
- Selin Öztekin
- Department of Medical Oncology, Erasmus Medical Center (MC) Cancer Institute, Rotterdam, the Netherlands
| | - Maartje J Hooning
- Department of Medical Oncology, Erasmus Medical Center (MC) Cancer Institute, Rotterdam, the Netherlands
| | | | - Anne-Marie H P Dietvorst
- Department of Medical Oncology, Breast Cancer Center South Holland South, Van Weel Bethesda Hospital, Dirksland, the Netherlands
| | - Jan C Drooger
- Department of Medical Oncology, Breast Cancer Center South Holland South, Ikazia Hospital, Rotterdam, the Netherlands
| | - Jos J E M Kitzen
- Department of Medical Oncology, Albert Schweitzer Hospital, Dordrecht, the Netherlands
| | - John W M Martens
- Department of Medical Oncology, Erasmus Medical Center (MC) Cancer Institute, Rotterdam, the Netherlands
| | | | - Mijntje B Vastbinder
- Department of Medical Oncology, IJsselland Hospital, Capelle aan den IJssel, the Netherlands
| | - Hanneke Zuetenhorst
- Department of Medical Oncology, Franciscus Gasthuis en Vlietland, Rotterdam, the Netherlands
| | | | - Agnes Jager
- Department of Medical Oncology, Erasmus Medical Center (MC) Cancer Institute, Rotterdam, the Netherlands
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6
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Alvarez-Frutos L, Barriuso D, Duran M, Infante M, Kroemer G, Palacios-Ramirez R, Senovilla L. Multiomics insights on the onset, progression, and metastatic evolution of breast cancer. Front Oncol 2023; 13:1292046. [PMID: 38169859 PMCID: PMC10758476 DOI: 10.3389/fonc.2023.1292046] [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] [Received: 09/10/2023] [Accepted: 11/23/2023] [Indexed: 01/05/2024] Open
Abstract
Breast cancer is the most common malignant neoplasm in women. Despite progress to date, 700,000 women worldwide died of this disease in 2020. Apparently, the prognostic markers currently used in the clinic are not sufficient to determine the most appropriate treatment. For this reason, great efforts have been made in recent years to identify new molecular biomarkers that will allow more precise and personalized therapeutic decisions in both primary and recurrent breast cancers. These molecular biomarkers include genetic and post-transcriptional alterations, changes in protein expression, as well as metabolic, immunological or microbial changes identified by multiple omics technologies (e.g., genomics, epigenomics, transcriptomics, proteomics, glycomics, metabolomics, lipidomics, immunomics and microbiomics). This review summarizes studies based on omics analysis that have identified new biomarkers for diagnosis, patient stratification, differentiation between stages of tumor development (initiation, progression, and metastasis/recurrence), and their relevance for treatment selection. Furthermore, this review highlights the importance of clinical trials based on multiomics studies and the need to advance in this direction in order to establish personalized therapies and prolong disease-free survival of these patients in the future.
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Affiliation(s)
- Lucia Alvarez-Frutos
- Laboratory of Cell Stress and Immunosurveillance, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid – Centro Superior de Investigaciones Cientificas (CSIC), Valladolid, Spain
| | - Daniel Barriuso
- Laboratory of Cell Stress and Immunosurveillance, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid – Centro Superior de Investigaciones Cientificas (CSIC), Valladolid, Spain
| | - Mercedes Duran
- Laboratory of Molecular Genetics of Hereditary Cancer, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid – Centro Superior de Investigaciones Cientificas (CSIC), Valladolid, Spain
| | - Mar Infante
- Laboratory of Molecular Genetics of Hereditary Cancer, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid – Centro Superior de Investigaciones Cientificas (CSIC), Valladolid, Spain
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
- Department of Biology, Institut du Cancer Paris CARPEM, Hôpital Européen Georges Pompidou, Paris, France
| | - Roberto Palacios-Ramirez
- Laboratory of Cell Stress and Immunosurveillance, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid – Centro Superior de Investigaciones Cientificas (CSIC), Valladolid, Spain
| | - Laura Senovilla
- Laboratory of Cell Stress and Immunosurveillance, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular (IBGM), Universidad de Valladolid – Centro Superior de Investigaciones Cientificas (CSIC), Valladolid, Spain
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France
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7
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Vahdatinia M, Derakhshan F, Da Cruz Paula A, Dopeso H, Marra A, Gazzo AM, Brown D, Selenica P, Ross DS, Razavi P, Zhang H, Weigelt B, Wen HY, Brogi E, Reis-Filho JS, Pareja F. KIT genetic alterations in breast cancer. J Clin Pathol 2023; 77:40-45. [PMID: 36323507 PMCID: PMC10151428 DOI: 10.1136/jcp-2022-208611] [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: 10/03/2022] [Accepted: 10/12/2022] [Indexed: 01/19/2023]
Abstract
AIMS Activating somatic mutations or gene amplification of KIT result in constitutive activation of its receptor tyrosine kinase, which is targetable in various solid tumours. Here, we sought to investigate the presence of KIT genetic alterations in breast cancer (BC) and characterise the histological and genomic features of these tumours. METHODS A retrospective analysis of 5,575 BCs previously subjected to targeted sequencing using the FDA-authorised Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay was performed to identify BCs with KIT alterations. A histological assessment of KIT-altered BCs was conducted, and their repertoire of genetic alterations was compared with that of BCs lacking KIT genetic alterations, matched for age, histological type, oestrogen receptor/HER2 status and sample type. RESULTS We identified 18 BCs (0.32%), including 9 primary and 9 metastatic BCs, with oncogenic/likely oncogenic genetic alterations affecting KIT, including activating somatic mutations (n=4) or gene amplification (n=14). All KIT-altered BCs were of high histological grade, although no distinctive histological features were observed. When compared with BCs lacking KIT genetic alterations, no distinctive genetic features were identified. In two metastatic KIT-altered BCs in which the matched primary BC had also been analysed by MSK-IMPACT, the KIT mutations were found to be restricted to the metastatic samples, suggesting that they were late events in the evolution of these cancers. CONCLUSIONS KIT genetic alterations are vanishingly rare in BC. KIT-altered BCs are of high grade but lack distinctive histological features. Genetic alterations in KIT might be late events in the evolution and/or progression of BC.
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Affiliation(s)
- Mahsa Vahdatinia
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Fatemeh Derakhshan
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Arnaud Da Cruz Paula
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Higinio Dopeso
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Antonio Marra
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Andrea M Gazzo
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - David Brown
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Pier Selenica
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Dara S Ross
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Pedram Razavi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Hong Zhang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Britta Weigelt
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Hannah Y Wen
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Edi Brogi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Jorge S Reis-Filho
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Fresia Pareja
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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8
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Sijnesael T, Richard F, Rätze MA, Koorman T, Bassey-Archibong B, Rohof C, Daniel J, Desmedt C, Derksen PW. Canonical Kaiso target genes define a functional signature that associates with breast cancer survival and the invasive lobular carcinoma histological type. J Pathol 2023; 261:477-489. [PMID: 37737015 DOI: 10.1002/path.6205] [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: 01/10/2023] [Revised: 07/07/2023] [Accepted: 08/17/2023] [Indexed: 09/23/2023]
Abstract
Invasive lobular carcinoma (ILC) is a low- to intermediate-grade histological breast cancer type caused by mutational inactivation of E-cadherin function, resulting in the acquisition of anchorage independence (anoikis resistance). Most ILC cases express estrogen receptors, but options are limited in relapsed endocrine-refractory disease as ILC tends to be less responsive to standard chemotherapy. Moreover, ILC can relapse after >15 years, an event that currently cannot be predicted. E-cadherin inactivation leads to p120-catenin-dependent relief of the transcriptional repressor Kaiso (ZBTB33) and activation of canonical Kaiso target genes. Here, we examined whether an anchorage-independent and ILC-specific transcriptional program correlated with clinical parameters in breast cancer. Based on the presence of a canonical Kaiso-binding consensus sequence (cKBS) in the promoters of genes that are upregulated under anchorage-independent conditions, we defined an ILC-specific anoikis resistance transcriptome (ART). Converting the ART genes into human orthologs and adding published Kaiso target genes resulted in the Kaiso-specific ART (KART) 33-gene signature, used subsequently to study correlations with histological and clinical variables in primary breast cancer. Using publicly available data for ERPOS Her2NEG breast cancer, we found that expression of KART was positively associated with the histological ILC breast cancer type (p < 2.7E-07). KART expression associated with younger patients in all invasive breast cancers and smaller tumors in invasive ductal carcinoma of no special type (IDC-NST) (<2 cm, p < 6.3E-10). We observed associations with favorable long-term prognosis in both ILC (hazard ratio [HR] = 0.51, 95% CI = 0.29-0.91, p < 3.4E-02) and IDC-NST (HR = 0.79, 95% CI = 0.66-0.93, p < 1.2E-04). Our analysis thus defines a new mRNA expression signature for human breast cancer based on canonical Kaiso target genes that are upregulated in E-cadherin deficient ILC. The KART signature may enable a deeper understanding of ILC biology and etiology. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Thijmen Sijnesael
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - François Richard
- Laboratory for Translational Breast Cancer Research, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Max Ak Rätze
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Thijs Koorman
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Christa Rohof
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Juliet Daniel
- Department of Biology, McMaster University, Hamilton, ON, Canada
| | - Christine Desmedt
- Laboratory for Translational Breast Cancer Research, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Patrick Wb Derksen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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9
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Porter BA, Frerich C, Lainé M, Clark AB, Durdana I, Lee J, Taya M, Sahoo S, Greene GL, Bennett L, Conzen SD. Glucocorticoid Receptor Activation in Lobular Breast Cancer Is Associated with Reduced Cell Proliferation and Promotion of Metastases. Cancers (Basel) 2023; 15:4679. [PMID: 37835373 PMCID: PMC10571671 DOI: 10.3390/cancers15194679] [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: 07/29/2023] [Revised: 08/31/2023] [Accepted: 09/18/2023] [Indexed: 10/15/2023] Open
Abstract
Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC's unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern of metastases to serosal membranes. Unlike invasive ductal carcinoma (IDC), ILC metastases often intercalate into the mesothelial layer of the peritoneum and other serosal surfaces. While ER activity is a known driver of ILC proliferation, very little is known about how additional nuclear receptors contribute to ILC's distinctive biology. In ER+ IDC, we showed previously that glucocorticoid receptor (GR) activity inhibits pro-proliferative gene expression and cell proliferation. Here we examined ER+ ILC models and found that GR activation similarly reduces S-phase entry gene expression and ILC proliferation. While slowing tumor growth rate, our data also suggest that GR activation results in an enhanced metastatic phenotype through increasing integrin-encoding gene expression, extracellular matrix protein adhesion, and mesothelial cell clearance. Moreover, in an intraductal mouse mammary gland model of ILC, we found that GR expression is associated with increased bone metastases despite slowed primary mammary tumor growth. Taken together, our findings suggest GR-mediated gene expression may contribute to the unusual characteristics of ILC biology.
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Affiliation(s)
- Baylee A. Porter
- Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Candace Frerich
- Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Muriel Lainé
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
| | - Abigail B. Clark
- Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ishrat Durdana
- Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jeon Lee
- Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Manisha Taya
- Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sunati Sahoo
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Geoffrey L. Greene
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
| | - Lynda Bennett
- Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Suzanne D. Conzen
- Department of Internal Medicine, Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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10
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Sflomos G, Schaumann N, Christgen M, Christgen H, Bartels S, Kreipe H, Battista L, Brisken C. Optimized Modeling of Metastatic Triple-Negative Invasive Lobular Breast Carcinoma. Cancers (Basel) 2023; 15:3299. [PMID: 37444409 DOI: 10.3390/cancers15133299] [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: 05/09/2023] [Revised: 06/07/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
Invasive lobular carcinoma (ILC) is a common breast cancer subtype that is often diagnosed at advanced stages and causes significant morbidity. Late-onset secondary tumor recurrence affects up to 30% of ILC patients, posing a therapeutic challenge if resistance to systemic therapy develops. Nonetheless, there is a lack of preclinical models for ILC, and the current models do not accurately reproduce the complete range of the disease. We created clinically relevant metastatic xenografts to address this gap by grafting the triple-negative IPH-926 cell line into mouse milk ducts. The resulting intraductal xenografts accurately recapitulate lobular carcinoma in situ (LCIS), invasive lobular carcinoma, and metastatic ILC in relevant organs. Using a panel of 15 clinical markers, we characterized the intratumoral heterogeneity of primary and metastatic lesions. Interestingly, intraductal IPH-926 xenografts express low but actionable HER2 and are not dependent on supplementation with the ovarian hormone estradiol for their growth. This model provides a valuable tool to test the efficiency of potential new ILC therapeutics, and it may help detect vulnerabilities within ILC that can be exploited for therapeutic targeting.
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Affiliation(s)
- George Sflomos
- ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Nora Schaumann
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Matthias Christgen
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Henriette Christgen
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Stephan Bartels
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Hans Kreipe
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Laura Battista
- ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
| | - Cathrin Brisken
- ISREC-Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
- Institute of Pathology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
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11
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Luo J, Zou H, Guo Y, Tong T, Chen Y, Xiao Y, Pan Y, Li P. The oncogenic roles and clinical implications of YAP/TAZ in breast cancer. Br J Cancer 2023; 128:1611-1624. [PMID: 36759723 PMCID: PMC10133323 DOI: 10.1038/s41416-023-02182-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 01/16/2023] [Accepted: 01/23/2023] [Indexed: 02/11/2023] Open
Abstract
Breast cancer (BC) is the most commonly diagnosed form of cancer and a leading cause of cancer-related deaths among women worldwide. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are homologous transcriptional coactivators and downstream effectors of Hippo signalling. YAP/TAZ activation has been revealed to play essential roles in multiple events of BC development, including tumour initiation, progression, metastasis, drug resistance and stemness regulations. In this review, we will first give an overview of YAP/TAZ-mediated oncogenesis in BC, and then systematically summarise the oncogenic roles of YAP/TAZ in various BC subtypes, BC stem cells (BCSCs) and tumour microenvironments (TMEs). Based on these findings, we will further discuss the clinical implications of YAP/TAZ-based targeted therapies in BC and the potential future direction.
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Affiliation(s)
- Juan Luo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Hailin Zou
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Yibo Guo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Tongyu Tong
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China.,Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Yun Chen
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Yunjun Xiao
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China
| | - Yihang Pan
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China. .,Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China.
| | - Peng Li
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China. .,Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, People's Republic of China.
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12
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Oesterreich S, Nasrazadani A, Zou J, Carleton N, Onger T, Wright MD, Li Y, Demanelis K, Ramaswamy B, Tseng G, Lee AV, Williams N, Kruse M. Clinicopathological Features and Outcomes Comparing Patients With Invasive Ductal and Lobular Breast Cancer. J Natl Cancer Inst 2022; 114:1511-1522. [PMID: 36239760 PMCID: PMC9664185 DOI: 10.1093/jnci/djac157] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 06/16/2022] [Accepted: 08/03/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND There is increasing interest in better understanding the biology and clinical presentation of invasive lobular cancer (ILC), which is the most common special histological subtype of breast cancer. Limited large contemporary data sets are available allowing comparison of clinicopathologic features between ILC and invasive ductal cancer (IDC). METHODS The Great Lakes Breast Cancer Consortium was formed to compare clinical behavior of ILC (n = 3617) and IDC (n = 30 045) from 33 662 patients treated between 1990 and 2017 at 3 large clinical centers. We used Kaplan-Meier analysis, Cox proportional hazards modeling, and propensity score matching to evaluate treatment differences and outcomes. All statistical testing used 2-sided P values. RESULTS Compared with IDC, patients with ILC were more frequently diagnosed at later stages and with more lymph node involvement (corrected P < .001). Estrogen receptor-positive ILCs were of lower grade (grade 1 and 2: 90% in ILC vs 72% in IDC) but larger in size (T3 and 4: 14.3% in ILC vs 3.4% in IDC) (corrected P < .001), and since 1990, the mean ILC size detected at diagnosis increased yearly. Patients with estrogen receptor (ER)-positive ILC underwent statistically significantly more mastectomies compared with ER-positive IDC (57% vs 46%). Using Kaplan-Meier analysis, patients with ER-positive ILC had statistically significantly worse disease-free survival and overall survival than ER-positive IDC although 6 times more IDCs were classified as high risk by OncotypeDx Breast Recurrence Score assay. CONCLUSIONS This large, retrospective, collaborative analysis with 3 clinical centers identified meaningful differences in clinicopathological features between ILC and IDC, providing further evidence that these are 2 different entities requiring different clinical management.
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Affiliation(s)
- Steffi Oesterreich
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Women’s Research Institute and Women’s Cancer Research Center, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Azadeh Nasrazadani
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Women’s Research Institute and Women’s Cancer Research Center, Pittsburgh, PA, USA
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jian Zou
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Neil Carleton
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Women’s Research Institute and Women’s Cancer Research Center, Pittsburgh, PA, USA
- Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Tiffany Onger
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
| | | | - Yujia Li
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Bhuvaneswari Ramaswamy
- James Cancer Hospital, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - George Tseng
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Adrian V Lee
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA
- Magee-Women’s Research Institute and Women’s Cancer Research Center, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nicole Williams
- James Cancer Hospital, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Megan Kruse
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
- Case Western Comprehensive Cancer Center, Cleveland, OH, USA
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13
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Perry G, Dadiani M, Kahana‐Edwin S, Pavlovski A, Markus B, Hornung G, Balint‐Lahat N, Yosepovich A, Hout‐Siloni G, Jacob‐Hirsch J, Sklair‐Levy M, Friedman E, Barshack I, Kaufman B, Gal‐Yam EN, Paluch‐Shimon S. Divergence of mutational signatures in association with breast cancer subtype. Mol Carcinog 2022; 61:1056-1070. [DOI: 10.1002/mc.23461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/04/2022] [Accepted: 08/29/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Gili Perry
- Cancer Research Center, Sheba Medical Center Tel‐Hashomer Israel
| | - Maya Dadiani
- Cancer Research Center, Sheba Medical Center Tel‐Hashomer Israel
- The Nehemia Rubin Excellence in Biomedical Research – The TELEM Program, supported by the Aaron Gutwirth Fund Tel‐Hashomer Israel
| | | | - Anya Pavlovski
- Pathology Institute, Sheba Medical Center Tel‐Hashomer Israel
| | - Barak Markus
- The Nancy & Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science Rehovot Israel
| | - Gil Hornung
- The Nancy & Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science Rehovot Israel
| | | | - Ady Yosepovich
- Pathology Institute, Sheba Medical Center Tel‐Hashomer Israel
| | - Goni Hout‐Siloni
- Cancer Research Center, Sheba Medical Center Tel‐Hashomer Israel
| | | | - Miri Sklair‐Levy
- Department of Diagnostic Radiology Sheba Medical Center Tel‐Hashomer Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
| | - Eitan Friedman
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Sheba Medical Center, The Susanne Levy Gertner Oncogenetics Unit Tel‐Hashomer Israel
| | - Iris Barshack
- Pathology Institute, Sheba Medical Center Tel‐Hashomer Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
| | - Bella Kaufman
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Breast Oncology Institute, Sheba Medical Center Tel‐Hashomer Israel
| | - Einav Nili Gal‐Yam
- Breast Oncology Institute, Sheba Medical Center Tel‐Hashomer Israel
- The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center Ramat Gan Israel
| | - Shani Paluch‐Shimon
- Breast Oncology Institute, Sheba Medical Center Tel‐Hashomer Israel
- Sharett Institute of Oncology Hadassah University Hospital and Faculty of Medicine, Hebrew University Jerusalem Israel
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14
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Loss of E-cadherin leads to Id2-dependent inhibition of cell cycle progression in metastatic lobular breast cancer. Oncogene 2022; 41:2932-2944. [PMID: 35437308 PMCID: PMC9122823 DOI: 10.1038/s41388-022-02314-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 03/30/2022] [Accepted: 04/01/2022] [Indexed: 12/30/2022]
Abstract
Invasive lobular breast carcinoma (ILC) is characterized by proliferative indolence and long-term latency relapses. This study aimed to identify how disseminating ILC cells control the balance between quiescence and cell cycle re-entry. In the absence of anchorage, ILC cells undergo a sustained cell cycle arrest in G0/G1 while maintaining viability. From the genes that are upregulated in anchorage independent ILC cells, we selected Inhibitor of DNA binding 2 (Id2), a mediator of cell cycle progression. Using loss-of-function experiments, we demonstrate that Id2 is essential for anchorage independent survival (anoikis resistance) in vitro and lung colonization in mice. Importantly, we find that under anchorage independent conditions, E-cadherin loss promotes expression of Id2 in multiple mouse and (organotypic) human models of ILC, an event that is caused by a direct p120-catenin/Kaiso-dependent transcriptional de-repression of the canonical Kaiso binding sequence TCCTGCNA. Conversely, stable inducible restoration of E-cadherin expression in the ILC cell line SUM44PE inhibits Id2 expression and anoikis resistance. We show evidence that Id2 accumulates in the cytosol, where it induces a sustained and CDK4/6-dependent G0/G1 cell cycle arrest through interaction with hypo-phosphorylated Rb. Finally, we find that Id2 is indeed enriched in ILC when compared to other breast cancers, and confirm cytosolic Id2 protein expression in primary ILC samples. In sum, we have linked mutational inactivation of E-cadherin to direct inhibition of cell cycle progression. Our work indicates that loss of E-cadherin and subsequent expression of Id2 drive indolence and dissemination of ILC. As such, E-cadherin and Id2 are promising candidates to stratify low and intermediate grade invasive breast cancers for the use of clinical cell cycle intervention drugs.
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15
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Allen V, Coulombe J, Zhao H, Kreps LM, Cook DP, Pryce B, Clemons M, Vanderhyden BC, Gray DA, Addison CL. VIVA1: a more invasive subclone of MDA-MB-134VI invasive lobular carcinoma cells with increased metastatic potential in xenograft models. Br J Cancer 2022; 127:56-68. [PMID: 35318435 PMCID: PMC9276762 DOI: 10.1038/s41416-022-01778-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 01/28/2022] [Accepted: 02/25/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Invasive lobular carcinoma (ILC) is the second most common type of breast cancer. As few tools exist to study ILC metastasis, we isolated ILC cells with increased invasive properties to establish a spontaneously metastasising xenograft model. METHODS MDA-MB-134VI ILC cells were placed in transwells for 7 days. Migrated cells were isolated and expanded to create the VIVA1 cell line. VIVA1 cells were compared to parental MDA-MB-134VI cells in vitro for ILC marker expression and relative proliferative and invasive ability. An intraductally injected orthotopic xenograft model was used to assess primary and metastatic tumour growth in vivo. RESULTS Similar to MDA-MB-134VI, VIVA1 cells retained expression of oestrogen receptor (ER) and lacked expression of E-cadherin, however showed increased invasion in vitro. Following intraductal injection, VIVA1 and MDA-MB-134VI cells had similar primary tumour growth and survival kinetics. However, macrometastases were apparent in 7/10 VIVA1-injected animals. Cells from a primary orthotopic tumour (VIVA-LIG43) were isolated and showed similar proliferative rates but were also more invasive than parental cells. Upon re-injection intraductally, VIVA-LIG43 cells had more rapid tumour growth with similar metastatic incidence and location. CONCLUSIONS We generated a new orthotopic spontaneously metastasising xenograft model for ER+ ILC amenable for the study of ILC metastasis.
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Affiliation(s)
- Victoria Allen
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5, ON, Canada
| | - Josée Coulombe
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada
| | - Huijun Zhao
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada
| | - Lauren M Kreps
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5, ON, Canada
| | - David P Cook
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H 8M5, ON, Canada
| | - Benjamin Pryce
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H 8M5, ON, Canada
| | - Mark Clemons
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada.,Department of Medicine, University of Ottawa, Ottawa, K1H 8M5, ON, Canada
| | - Barbara C Vanderhyden
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, K1H 8M5, ON, Canada
| | - Douglas A Gray
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada.,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5, ON, Canada
| | - Christina L Addison
- Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6, ON, Canada. .,Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5, ON, Canada. .,Department of Medicine, University of Ottawa, Ottawa, K1H 8M5, ON, Canada.
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16
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Weiser R, Polychronopoulou E, Hatch SS, Haque W, Ghani HA, He J, Kuo YF, Gradishar WJ, Klimberg VS. Adjuvant chemotherapy in patients with invasive lobular carcinoma and use of the 21-gene recurrence score: A National Cancer Database analysis. Cancer 2022; 128:1738-1747. [PMID: 35137951 DOI: 10.1002/cncr.34127] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 12/04/2021] [Accepted: 12/22/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Invasive lobular carcinoma (ILC) is traditionally considered less responsive to chemotherapy. Although the Oncotype recurrence score (RS) has been validated to identify high-risk patients who benefit from chemotherapy, some studies have questioned its relevance in patients with ILC. The objective of this study was to better characterize potential use of the RS in these patients. METHODS The National Cancer Database was used to identify women with stage I through III, T1 through T3, N0 or N1, hormone receptor-positive, HER2-negative ILC or invasive ductal carcinoma (IDC) who had an available RS between 2010 and 2016. Multivariable Cox regression was used to model the effect of variables on 5-year overall survival (OS). The Kaplan-Meier method was used to estimate OS according to the RS, nodal status, and chemotherapy. RESULTS In total, 15,763 patients with ILC and 100,070 with IDC were identified. The mean age of patients with ILC and IDC was 59.2 ± 9.1 and 57.2 ± 9.8, respectively. A lower percentage of patients with ILC versus those with IDC had a high RS, defined as >25 (6.6% vs 16.0%; P < .0001). ILC patients with a high RS who had N0 or N1 disease received approximately 10% less chemotherapy compared with similar patients who had IDC. The results indicated that the RS had statistically significant prognostic value for patients with ILC. In addition, an absolute OS advantage was correlated with the receipt of chemotherapy by patients with ILC who had a high RS with N0 or N1 disease. CONCLUSIONS Patients with ILC who have a high RS are treated less often with chemotherapy compared with similar patients who have IDC. Nevertheless, the RS has a prognostic as well as a predictive value in ILC, with an association between OS benefit and chemotherapy receipt in patients who have ILC with a high RS, especially if they have N1 disease. LAY SUMMARY Invasive lobular carcinoma (ILC) is a subtype of breast cancer comprising about 15% of cases. The Oncotype recurrence score (RS) is a genetic test of breast tumors that helps predict which patients might benefit from chemotherapy. Some have doubted the relevance of the RS for patients with ILC. In this study, the authors show that the RS is relevant for patients who have ILC. The RS has the potential of predicting the risk of recurrence and identifying patients with ILC who might benefit from chemotherapy.
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Affiliation(s)
- Roi Weiser
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Efstathia Polychronopoulou
- Department of Preventive Medicine and Population Health, Office of Biostatistics, University of Texas Medical Branch, Galveston, Texas
| | - Sandra S Hatch
- Department of Radiation Oncology, University of Texas Medical Branch, Galveston, Texas.,Deptartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Waqar Haque
- Department of Radiation Oncology, Houston Methodist Hospital, Houston, Texas
| | - Hafiz A Ghani
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Jing He
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas
| | - Yong-Fang Kuo
- Department of Preventive Medicine and Population Health, Office of Biostatistics, University of Texas Medical Branch, Galveston, Texas
| | - William J Gradishar
- Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - V Suzanne Klimberg
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas.,Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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17
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Zhao CM, Li LL, Xu JW, Li ZW, Shi P, Jiang R. LINC00092 Suppresses the Malignant Progression of Breast Invasive Ductal Carcinoma Through Modulating SFRP1 Expression by Sponging miR-1827. Cell Transplant 2022; 31:9636897221086967. [PMID: 35343265 PMCID: PMC8958677 DOI: 10.1177/09636897221086967] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Breast invasive ductal carcinoma (IDC) is a most common kind of breast cancer (BC), yet to date the corresponding effective therapies are limited. Extensive evidence has indicated that lncRNAs are involved in multiple cancers, and the potential mechanism of lncRNAs, such as LINC00092, mentioned in IDC remains elusive. IDC clinical samples from TCGA database were used to analyze the expression levels of LINC00092, miR-1827 and SFRP1. Kaplan-Meier method was applied to plot the overall survival curves. KEGG and GO were employed to screen the pathway that LINC00092 participated in. Pearson’s correlation analysis determined the relationship between LINC00092 and SFRP1. Bioinformatics analysis and dual-luciferase reporter assay examined the association among LINC00092, miR-1827, and SFRP1. Cell counting kit-8, colony formation and transwell assays were performed to detect cell viability, colony formation, and migration and invasion, respectively. Quantitative reverse-transcription polymerase chain reaction and western blot were utilized to investigate the expression at RNA and protein levels. LINC00092 expression was down-regulated in IDC tissues and cells, which was correlated with poor prognosis. Down-regulated LINC00092 facilitated cell proliferation, colony formation, and cell migration and invasion, while up-regulated LINC00092 inhibited cell malignant behaviors. LINC00092/SFRP1 physically bound to miR-1827 in IDC. SFRP1 expression was proportional to LINC00092 expression and inversely proportional to miR-1827 expression. The inhibitory effects of LINC00092 on cell aggressive behaviors were partially regulated by miR-1827/SFRP1. In summary, our results indicated that overexpression of LINC00092 inhibited the development of IDC through modulating miR-1827/SFRP1 axis, suggesting new therapeutic targets to treat IDC.
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Affiliation(s)
- Chun-Ming Zhao
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Lin-Lin Li
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jia-Wen Xu
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhi-Wei Li
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Peng Shi
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Rui Jiang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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18
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Oluyemi E, Peshtani A, White MJ, Cimino-Mathews A. Radiologic and Pathologic Correlation of Invasive Lobular Carcinoma of the Breast. CURRENT BREAST CANCER REPORTS 2021. [DOI: 10.1007/s12609-021-00434-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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19
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Sflomos G, Schipper K, Koorman T, Fitzpatrick A, Oesterreich S, Lee AV, Jonkers J, Brunton VG, Christgen M, Isacke C, Derksen PWB, Brisken C. Atlas of Lobular Breast Cancer Models: Challenges and Strategic Directions. Cancers (Basel) 2021; 13:5396. [PMID: 34771558 PMCID: PMC8582475 DOI: 10.3390/cancers13215396] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 12/14/2022] Open
Abstract
Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancer (BC) cases and responds well to endocrine treatment when estrogen receptor α-positive (ER+) yet differs in many biological aspects from other ER+ BC subtypes. Up to 30% of patients with ILC will develop late-onset metastatic disease up to ten years after initial tumor diagnosis and may experience failure of systemic therapy. Unfortunately, preclinical models to study ILC progression and predict the efficacy of novel therapeutics are scarce. Here, we review the current advances in ILC modeling, including cell lines and organotypic models, genetically engineered mouse models, and patient-derived xenografts. We also underscore four critical challenges that can be addressed using ILC models: drug resistance, lobular tumor microenvironment, tumor dormancy, and metastasis. Finally, we highlight the advantages of shared experimental ILC resources and provide essential considerations from the perspective of the European Lobular Breast Cancer Consortium (ELBCC), which is devoted to better understanding and translating the molecular cues that underpin ILC to clinical diagnosis and intervention. This review will guide investigators who are considering the implementation of ILC models in their research programs.
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Affiliation(s)
- George Sflomos
- ISREC—Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
| | - Koen Schipper
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK; (K.S.); (A.F.); (C.I.)
| | - Thijs Koorman
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (T.K.); (P.W.B.D.)
| | - Amanda Fitzpatrick
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK; (K.S.); (A.F.); (C.I.)
| | - Steffi Oesterreich
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA; (S.O.); (A.V.L.)
- Magee Women’s Cancer Research Institute, Pittsburgh, PA 15213, USA
- Cancer Biology Program, Women’s Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
| | - Adrian V. Lee
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA; (S.O.); (A.V.L.)
- Magee Women’s Cancer Research Institute, Pittsburgh, PA 15213, USA
- Cancer Biology Program, Women’s Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
| | - Jos Jonkers
- Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands;
- Oncode Institute, 1066 CX Amsterdam, The Netherlands
| | - Valerie G. Brunton
- Edinburgh Cancer Research UK Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK;
| | - Matthias Christgen
- Institute of Pathology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany;
| | - Clare Isacke
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK; (K.S.); (A.F.); (C.I.)
| | - Patrick W. B. Derksen
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; (T.K.); (P.W.B.D.)
| | - Cathrin Brisken
- ISREC—Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK; (K.S.); (A.F.); (C.I.)
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Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors. Cancers (Basel) 2021; 13:cancers13153695. [PMID: 34359596 PMCID: PMC8345067 DOI: 10.3390/cancers13153695] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/15/2021] [Accepted: 07/18/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Invasive lobular breast cancer (ILC) is a special type of breast cancer (BC) that was first described in 1941. The diagnosis of ILC is made by microscopy of tumor specimens, which reveals a distinct morphology. This review recapitulates the developments in the microscopic assessment of ILC from 1941 until today. We discuss different concepts of ILC, provide an overview on ILC variants, and highlight advances which have contributed to a better understanding of ILC as a special histologic spectrum of tumors. Abstract Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in CDH1-deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research.
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21
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Bergeron A, MacGrogan G, Bertaut A, Ladoire S, Arveux P, Desmoulins I, Bonnefoi H, Loustalot C, Auriol S, Beltjens F, Degrolard-Courcet E, Charon-Barra C, Richard C, Boidot R, Arnould L. Triple-negative breast lobular carcinoma: a luminal androgen receptor carcinoma with specific ESRRA mutations. Mod Pathol 2021; 34:1282-1296. [PMID: 33753865 PMCID: PMC8216909 DOI: 10.1038/s41379-021-00742-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/12/2022]
Abstract
Primary triple-negative invasive lobular breast carcinomas (TN-ILCs), which do not express hormone receptors and HER2 at diagnosis, are rare and poorly known. In this study, we analyzed the largest TN-ILC series ever reported in the literature, in comparison to phenotypically similar breast tumor subtypes: triple-negative invasive ductal carcinoma (TN-IDC) and hormone receptor-positive invasive lobular carcinoma (HR + ILC). All primary TN-ILCs registered in our database between 2000 and 2018 (n = 38) were compared to tumors from control groups, matched by stage and Elston/Ellis grade, with regard to clinical, pathologic, and immunohistochemical characteristics. A comparative molecular analysis (whole-exome and RNA sequencing using next-generation technology) was also performed. We found that TN-ILC patients were older than those with HR + ILC (P = 0.002) or TN-IDC (P < 0.001). Morphologically, TN-ILCs had aggressive phenotypes, with more pleomorphism (P = 0.003) and higher nuclear grades than HR + ILCs (P = 0.009). Immunohistochemistry showed that TN-ILCs less frequently expressed basal markers (CK5/6, EGFR and SOX10) than TN-IDCs (P < 0.001), while androgen receptor (AR) positivity was more prevalent (P < 0.001). Survival curves analysis did not show differences between TN-ILC and TN-IDC patients, while overall and distant metastasis-free survival were significantly worse compared to those with HR + ILCs (P = 0.047 and P = 0.039, respectively). At a molecular level, we found that TN-ILCs had particular transcriptomic profiles, characterized by increased AR signaling, and associated with frequent alterations in the PI3K network and ERBB2. Interestingly, whole-exome analysis also identified three specific recurrent ESRRA hotspot mutations in these tumors, which have never been described in breast cancer to date and which were absent in the other two tumor subtypes. Our findings highlight that TN-ILC is a unique aggressive breast cancer associated with elderly age, which belong to the luminal androgen receptor subtype as determined by immunohistochemistry and transcriptomic profiling. Moreover, it harbors specific molecular alterations (PI3K, ERBB2 and ESRRA) which may pave the way for new targeted therapeutic strategies.
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Affiliation(s)
- Anthony Bergeron
- Unit of Pathology, Department of Biology and Pathology of the Tumors, Centre Georges-François Leclerc, Dijon, France.
| | - Gaëtan MacGrogan
- Department of Biopathology, Institut Bergonié, Bordeaux, France
- INSERM U1218, Bordeaux, France
| | - Aurélie Bertaut
- Unit of Methodology and Biostatistics, Centre Georges-François Leclerc, Dijon, France
| | - Sylvain Ladoire
- Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France
- INSERM U1231, Dijon, France
- University of Burgundy-Franche Comté, Dijon, France
| | - Patrick Arveux
- Department of Epidemiology, Centre Georges-François Leclerc, Dijon, France
| | - Isabelle Desmoulins
- Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France
| | - Hervé Bonnefoi
- INSERM U1218, Bordeaux, France
- Department of Medical Oncology, Institut Bergonié, Bordeaux, France
- University of Bordeaux, Bordeaux, France
| | | | - Sophie Auriol
- Department of Surgery, Institut Bergonié, Bordeaux, France
| | - Françoise Beltjens
- Unit of Pathology, Department of Biology and Pathology of the Tumors, Centre Georges-François Leclerc, Dijon, France
| | - Emilie Degrolard-Courcet
- Unit of Pathology, Department of Biology and Pathology of the Tumors, Centre Georges-François Leclerc, Dijon, France
| | - Céline Charon-Barra
- Unit of Pathology, Department of Biology and Pathology of the Tumors, Centre Georges-François Leclerc, Dijon, France
| | - Corentin Richard
- Unit of Molecular Pathology, Department of Biology and Pathology of the Tumors, Centre Georges-François Leclerc, Dijon, France
| | - Romain Boidot
- Unit of Molecular Pathology, Department of Biology and Pathology of the Tumors, Centre Georges-François Leclerc, Dijon, France
| | - Laurent Arnould
- Unit of Pathology, Department of Biology and Pathology of the Tumors, Centre Georges-François Leclerc, Dijon, France
- INSERM U1231, Dijon, France
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22
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Invasive Lobular Carcinoma of the Breast: Ongoing Trials, Challenges, and Future Directions. CURRENT BREAST CANCER REPORTS 2021. [DOI: 10.1007/s12609-021-00412-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Abstract
Purpose of Review
Invasive lobular carcinoma (ILC) is increasingly recognized as a distinct subtype of breast cancer with unique management challenges. We reviewed currently available clinical trials for patients with ILC.
Recent Findings
We describe the rationale for and study design of clinical trials for patients with both early stage and metastatic ILC. Molecular alterations specific to or enriched in ILC may serve as treatment targets.
Summary
ILC has specific features that may be treatment targets. Clinical trials for ILC are available and being developed.
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Mukhtar RA, Hoskin TL, Habermann EB, Day CN, Boughey JC. Changes in Management Strategy and Impact of Neoadjuvant Therapy on Extent of Surgery in Invasive Lobular Carcinoma of the Breast: Analysis of the National Cancer Database (NCDB). Ann Surg Oncol 2021; 28:5867-5877. [PMID: 33687613 PMCID: PMC8460506 DOI: 10.1245/s10434-021-09715-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 01/26/2021] [Indexed: 11/19/2022]
Abstract
Background Given reports of low response rates to neoadjuvant chemotherapy (NAC) in invasive lobular carcinoma (ILC), we evaluated whether use of alternative strategies such as neoadjuvant endocrine therapy (NET) is increasing. Additionally, we investigated whether NET is associated with more breast conservation surgery (BCS) and less extensive axillary surgery in those with ILC. Patients and Methods We queried the NCDB from 2010 to 2016 and identified all women with stage I–III hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2−) ILC who underwent surgery. We used Cochrane–Armitage tests to evaluate trends in utilization of the following treatment strategies: NAC, short-course NET, long-course NET, and primary surgery. We compared rates of BCS and extent of axillary surgery stratified by clinical stage and tumor receptor subtype for each treatment strategy. Results Among 69,312 cases of HR+/HER2− ILC, NAC use decreased slightly (from 4.7 to 4.2%, p = 0.007), while there was a small but significant increase in long-course NET (from 1.6 to 2.7%, p < 0.001). Long-course NET was significantly associated with increased BCS in patients with cT2–cT4 disease and less extensive axillary surgery in clinically node positive patients with HR+/HER2− tumors. Conclusions Primary surgery remains the most common treatment strategy in patients with ILC. However, NAC use decreased slightly over the study period, while the use of long-course NET had a small increase and was associated with more BCS and less extensive axillary surgery.
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Affiliation(s)
- Rita A Mukhtar
- Department of Surgery, University of California, San Francisco, CA, USA.
| | - Tanya L Hoskin
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Elizabeth B Habermann
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.,Department of Surgery, Mayo Clinic, Rochester, MN, USA.,Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | - Courtney N Day
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
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Imaging of Breast Cancers With Predilection for Nonmass Pattern of Growth: Invasive Lobular Carcinoma and DCIS-Does Imaging Capture It All? AJR Am J Roentgenol 2020; 215:1504-1511. [PMID: 33021831 DOI: 10.2214/ajr.19.22027] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE. Invasive lobular carcinoma (ILC) and ductal carcinoma in situ (DCIS) are distinct histopathologic entities with several commonalities: both have subtle clinical and imaging presentation, have been linked with controversy regarding optimal imaging techniques and management, and exemplify the codependence of adequate imaging evaluation and optimal treatment strategies in breast care. CONCLUSION. We review molecular mechanisms and histopathologic patterns that define the biologic behavior of both ILC and DCIS and discuss how these mechanisms translate into distinct clinical and imaging presentations that affect the staging workup and patient management algorithm.
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25
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Narbe U, Bendahl PO, Aaltonen K, Fernö M, Forsare C, Jørgensen CLT, Larsson AM, Rydén L. The Distribution of Circulating Tumor Cells Is Different in Metastatic Lobular Compared to Ductal Carcinoma of the Breast-Long-Term Prognostic Significance. Cells 2020; 9:E1718. [PMID: 32709042 PMCID: PMC7407940 DOI: 10.3390/cells9071718] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 07/13/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Invasive lobular carcinoma (ILC) has distinguishing features when compared to invasive ductal carcinoma of no special type (NST). In this study, we explored the distributional and prognostic characteristics of circulating tumor cells (CTCs) in metastatic ILC and NST. MATERIALS AND METHODS Patients were included in an observational trial (ClinicalTrials.gov NCT01322893) with ILC (n = 28) and NST (n = 111). CTC count (number/7.5 mL blood) was evaluated with serial sampling (CellSearch). The primary endpoint was progression-free survival (PFS). RESULTS The CTC counts were higher in ILC (median 70) than in NST cases (median 2) at baseline (p < 0.001). The evidence for ≥5 CTCs as a prognostic factor for PFS in ILC was weak, but stronger with higher cut-offs (CTC ≥ 20: hazard ratio (HR) 3.0, p = 0.01) (CTC ≥ 80: HR 3.6, p = 0.004). In NST, however, the prognostic effect of CTCs ≥5 was strong. Decline in CTC count from baseline to three months was associated with improved prognosis in ILC and NST. CONCLUSIONS The number of CTCs is higher in ILC than in NST, implying that a higher CTC cut-off could be considered for ILC when applying the CellSearch technique.
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Affiliation(s)
- Ulrik Narbe
- Department of Clinical Sciences, Division of Oncology, Lund University, SE-223 81 Lund, Sweden; (U.N.); (P.-O.B.); (M.F.); (C.F.); (C.L.T.J.); (A.-M.L.)
- Department of Oncology, Växjö Central Hospital, SE-352 34 Växjö, Sweden
| | - Pär-Ola Bendahl
- Department of Clinical Sciences, Division of Oncology, Lund University, SE-223 81 Lund, Sweden; (U.N.); (P.-O.B.); (M.F.); (C.F.); (C.L.T.J.); (A.-M.L.)
| | - Kristina Aaltonen
- Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, SE-223 81 Lund, Sweden;
| | - Mårten Fernö
- Department of Clinical Sciences, Division of Oncology, Lund University, SE-223 81 Lund, Sweden; (U.N.); (P.-O.B.); (M.F.); (C.F.); (C.L.T.J.); (A.-M.L.)
| | - Carina Forsare
- Department of Clinical Sciences, Division of Oncology, Lund University, SE-223 81 Lund, Sweden; (U.N.); (P.-O.B.); (M.F.); (C.F.); (C.L.T.J.); (A.-M.L.)
| | - Charlotte Levin Tykjær Jørgensen
- Department of Clinical Sciences, Division of Oncology, Lund University, SE-223 81 Lund, Sweden; (U.N.); (P.-O.B.); (M.F.); (C.F.); (C.L.T.J.); (A.-M.L.)
| | - Anna-Maria Larsson
- Department of Clinical Sciences, Division of Oncology, Lund University, SE-223 81 Lund, Sweden; (U.N.); (P.-O.B.); (M.F.); (C.F.); (C.L.T.J.); (A.-M.L.)
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, SE-221 85 Lund, Sweden
| | - Lisa Rydén
- Department of Clinical Sciences, Division of Surgery, Lund University, SE-223 81 Lund, Sweden
- Department of Surgery, Skåne University Hospital, SE-221 85 Lund, Sweden
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Kee GJ, Tan RYC, Rehena S, Lee JJX, Zaw MWW, Lian WX, Yeong J, Tan SM, Lim SH, Tan BKT, Yap YS, Dent RA, Wong FY, Lee GE. Human epidermal growth factor receptor 2 positive rates in invasive lobular breast carcinoma: The Singapore experience. World J Clin Oncol 2020; 11:283-293. [PMID: 32728531 PMCID: PMC7360517 DOI: 10.5306/wjco.v11.i5.283] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/16/2020] [Accepted: 05/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Invasive lobular carcinomas (ILC) form 5%-10% of breast cancer and rarely show overexpression of human epidermal growth factor receptor 2 (HER2).
AIM To describe the prevalence and prognostic factors of HER2 positive (HER2+) ILC in an Asian population.
METHODS A retrospective review of patients with ILC seen between January 1985 and March 2018 at various SingHealth medical institutions was conducted. Demographic and clinical data were collected from medical records. We examined clinicopathological characteristics and survival in relation to HER2 status.
RESULTS A total of 864 patients were included. Prevalence of HER2 positivity was 10.1% (87 patients). Compared with HER2 negative (HER2-) ILC, HER2+ ILC was associated with a higher proportion of estrogen receptor negative (24.4% vs 5.9%, P < 0.001), progesterone receptor negative (PR-) (40.2% vs 24%, P = 0.002) and grade 3 tumours (Grade 3, 29.0% vs 10.2%, P < 0.001). Overall survival rate was poorer in patients with HER2+ compared to HER2- ILC (56.7% vs 72.9% alive at 10 years; hazard ratio 1.87, 95% confidence interval: 1.21-2.90, P = 0.004). Based on multivariate analysis, negative prognostic factors for overall survival included HER2 positivity, PR negativity, older age, Indian ethnicity and higher tumour stage.
CONCLUSION Prevalence of HER2+ ILC was 10.1%. HER2+ ILC was more likely to have poorer prognostic features such as estrogen receptor negative, PR- and higher tumour grade, and have a poorer survival.
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Affiliation(s)
- Ga-Jing Kee
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Ryan Ying-Cong Tan
- Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore
| | - Sultana Rehena
- Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Joycelyn Jie-Xin Lee
- Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore
| | - Ma Wai-Wai Zaw
- Department of Anaesthesiology, Singapore General Hospital, Singapore 169608, Singapore
| | - Wei-Xiang Lian
- Division of Radiation Oncology, National Cancer Centre, Singapore 169610, Singapore
| | - Joe Yeong
- Division of Pathology, Singapore General Hospital, Singapore 169608, Singapore
| | - Su-Ming Tan
- Division of Breast Surgery, Changi General Hospital, Singapore, 529889, Singapore
- SingHealth Duke-NUS Breast Centre, Singapore 169610, Singapore
| | - Swee-Ho Lim
- SingHealth Duke-NUS Breast Centre, Singapore 169610, Singapore
- Kandang Kerbau Breast Centre, Kandang Kerbau Women’s and Children’s Hospital, Singapore 229899, Singapore
| | - Benita Kiat-Tee Tan
- SingHealth Duke-NUS Breast Centre, Singapore 169610, Singapore
- Department of Breast Surgery, Singapore General Hospital, Singapore 169608, Singapore
| | - Yoon-Sim Yap
- Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore
| | | | - Fuh-Yong Wong
- Division of Radiation Oncology, National Cancer Centre, Singapore 169610, Singapore
| | - Guek-Eng Lee
- Division of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore
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Carbognin L, Simbolo M, Caliò A, Vicentini C, Delfino P, Sperduti I, Fassan M, Schettini F, Dieci MV, Griguolo G, Pilotto S, Fiorio E, Arpino G, Guarneri V, De Placido S, Conte P, Manfrin E, Brunelli M, Scambia G, Scarpa A, Tortora G, Bria E. Targeted next-generation sequencing identifies genomic abnormalities potentially driving the prognosis of early-stage invasive lobular breast carcinoma patients stratified according to a validated clinico-pathological model. Breast 2020; 50:56-63. [PMID: 32028173 PMCID: PMC7375560 DOI: 10.1016/j.breast.2020.01.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/14/2020] [Accepted: 01/20/2020] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION The clinico-pathological and molecular factors that drive the prognosis of invasive lobular breast carcinoma (ILC) are not entirely explored. In this regard, the development and validation of a prognostic model for ILC and the investigation of the distribution of molecular abnormalities (focusing on CDK4/6 alterations) according to prognosis were the aims of this study. PATIENTS AND METHODS Two clinico-pathological multi-center data-sets of early-stage ILC patients (Training/Validation Set, TS/VS) were gathered. A 3-class model was developed according to the multivariate analysis for disease-free-survival (DFS) and externally validated. Mutational, copy number variation and transcriptomic analyses by targeted next generation sequencing (NGS) were performed (and validated with quantitative PCR) in an explorative cohort of patients with poor and good prognosis. RESULTS Data from overall 773 patients (TS/VS: 491/282) were gathered. The developed model significantly discriminated low/intermediate/high risk in the TS (10-years DFS: 76.3%/67.6%/39.8%, respectively, p<0.0001) and in the VS (p<0.0001). In the explorative cohort for molecular analysis (34 patients), CDK4 gain was present exclusively in the poor prognosis group (35.0%, p = 0.03; OR 7.98, 95%CI 1.51-42.1, p = 0.014). Moreover, CDK4 and 6 overexpression showed a trend toward an association with poor prognosis (OR 2.7, 95%CI 0.4-18.1, p = 0.3; OR 3.29, 95%CI 0.56-19.25, p = 0.18). CONCLUSIONS A risk stratification model, able to accurately separate early-stage ILC patients' prognosis into different risk classes according to clinico-pathological variables, allowed to investigate potential biomarkers of prognosis with targeted NGS. CDK4 gain is suggested for future validation as a prognostic biomarker and a potential therapeutic opportunity in ILC patients.
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Affiliation(s)
- Luisa Carbognin
- University of Verona, Verona, Italy; Division of Gynecologic Oncology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Michele Simbolo
- Department of Diagnostics and Public Health, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Anna Caliò
- Department of Diagnostics and Public Health, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Caterina Vicentini
- ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy
| | - Pietro Delfino
- Department of Diagnostics and Public Health, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Isabella Sperduti
- Biostatistics, 'Regina Elena' National Cancer Institute, Roma, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padova, Padova, Italy
| | | | - Maria Vittoria Dieci
- Division of Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Gaia Griguolo
- Division of Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Sara Pilotto
- University of Verona, Verona, Italy; U.O.C. Medical Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Elena Fiorio
- U.O.C. Medical Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Grazia Arpino
- Medical Oncology, Federico II University, Napoli, Italy
| | - Valentina Guarneri
- Division of Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | | | - Pierfranco Conte
- Division of Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Erminia Manfrin
- Department of Diagnostics and Public Health, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Matteo Brunelli
- Department of Diagnostics and Public Health, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Giovanni Scambia
- Division of Gynecologic Oncology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy
| | - Giampaolo Tortora
- Oncologia Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Emilio Bria
- Oncologia Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Del Sacro Cuore, Roma, Italy.
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Wu J, Liu XJ, Hu JN, Liao XH, Lin FF. Transcriptomics and Prognosis Analysis to Identify Critical Biomarkers in Invasive Breast Carcinoma. Technol Cancer Res Treat 2020; 19:1533033820957011. [PMID: 33176622 PMCID: PMC7672771 DOI: 10.1177/1533033820957011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 07/08/2020] [Accepted: 08/18/2020] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE Invasive breast cancer (BRCA) is one of the prevalent types of invasive tumors with high mortality worldwide. Due to the lack of effective treatment to control the recurrence of distant metastases, the prognosis of BRCA is still very unsatisfactory. We aimed to find some biomarkers by bioinformatics analysis for survival prediction. METHODS Differentially expressed genes (DEGs) were screened out based on tumor group and normal group. Then, the weighted gene correlation network analysis (WGCNA) was employed to identify the clinically associated gene sets. Meanwhile, the enrichment analyses were performed for the functional annotation of the critical genes. The Kaplan Meier analysis calculated the essential genes' prognostic value. RESULTS After threshold screening, 1655 DEGs were obtained for subsequent analysis. 51 out of 1655 DEGs were significantly associated with BRCA patients' estrogen receptor status via WGCNA. Three genes (FABP7, CXCL3, and LOC284578) out of the 51 genes were associated with overall survival, and 3 genes were relapse-free survival associated. Finally, we obtained 5 essential prognostic associated genes (FABP7, CXCL3, LOC284578, CAPN6, and NRG2), which could be used as prognostic factors for BRCA. CONCLUSION Our findings obtained a gene module associated with BRCA clinical trait and several key genes that acted as essential components in the prognostic of cancer, which may improve its treatment.
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Affiliation(s)
- Jun Wu
- Pathology Department, The People’s Hospital of Lishui, Zhejiang, China
| | - Xiao-Jun Liu
- External Liaison Office, The Central Hospital of Lishui City, Zhejiang, China
| | - Jia-Nan Hu
- The Oncology Department, The People’s Hospital of Lishui, Zhejiang, China
| | - Xu-Hui Liao
- Pathology Department, The People’s Hospital of Lishui, Zhejiang, China
| | - Fei-Fei Lin
- Department of Clinical laboratory, The People’s Hospital of Lishui, Zhejiang, China
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29
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SNAIL is induced by tamoxifen and leads to growth inhibition in invasive lobular breast carcinoma. Breast Cancer Res Treat 2019; 175:327-337. [PMID: 30798422 DOI: 10.1007/s10549-019-05161-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 02/05/2019] [Indexed: 01/09/2023]
Abstract
PURPOSE Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer that is predominantly estrogen receptor alpha (ER)-positive (+) and is thus treated with endocrine therapies. Herein, we sought to understand the molecular underpinnings of the 4-hydroxytamoxifen (4OHT) resistance in ILC by assessing the potential role of the epithelial-to-mesenchymal transition transcription factor (EMT-TF) SNAIL (SNAI1). METHODS Using a series of breast cancer cell lines, we measured the basal, estrogen and 4OHT-induced expression of SNAIL and other EMT-TF family members by quantitative reverse transcription-polymerase chain reaction and immunoblotting. Chromatin immunoprecipitation experiments were performed to assess ER binding to the SNAIL promoter. Cell proliferation, cell cycle and apoptosis were assessed in 2D cultures. 3D growth was assessed in Matrigel and Collagen I cultures. RESULTS Estrogen and 4OHT induced SNAIL expression, but not that of the other EMT-TF family members SLUG (SNAI2) and SMUC (SNAI3), with the 4OHT effect being specific to the lobular but not the ductal subtype. We observed estrogen and 4OHT-induced ER recruitment to the SNAI1 promoter and high endogenous basal levels of SNAIL and several EMT-TFs in ILC cell lines. While SNAIL knockdown had a minor impact on the 4OHT partial agonism in estrogen-depleted conditions, it led to a surprising increase in cell proliferation in full serum. In complementary experiments, inducible SNAI1 overexpression caused decreased proliferation, associated with a cell cycle arrest in G0/G1. Additionally, apoptosis was observed in BCK4 cells. CONCLUSION These data suggest a previously unrecognized role for SNAIL in ILC, substantiating a context-dependent behavior for this EMT-TF.
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The estrogen receptor coactivator AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative invasive lobular carcinoma of the breast. Breast Cancer Res Treat 2019; 175:305-316. [PMID: 30796653 PMCID: PMC6533234 DOI: 10.1007/s10549-019-05138-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Accepted: 01/18/2019] [Indexed: 12/20/2022]
Abstract
Purpose According to the 2017 St Gallen surrogate definitions of the intrinsic subtypes, Ki67, progesterone receptor (PR) and Nottingham histological grade (NHG) are used for prognostic classification of estrogen receptor (ER) positive/HER2-negative breast cancer into luminal A- or luminal B-like. The aim of the present study was to investigate if additional biomarkers, related to endocrine signaling pathways, e.g., amplified in breast cancer 1 (AIB1), androgen receptor (AR), and G protein-coupled estrogen receptor (GPER), can provide complementary prognostic information in a subset of ER-positive/HER-negative invasive lobular carcinoma (ILC). Methods Biomarkers from 224 patients were analyzed immunohistochemically on tissue microarray. The primary endpoint was breast cancer mortality (BCM), analyzed with 10- and 25-year follow-up (FU). In addition, the prognostic value of gene expression data for these biomarkers was analyzed in three publicly available ILC datasets. Results AIB1 (high vs. low) was associated to BCM in multivariable analysis (adjusted for age, tumor size, nodal status, NHG, Ki67, luminal-like classification, and adjuvant systemic therapy) with 10-year FU (HR 6.8, 95% CI 2.3–20, P = 0.001) and 25-year FU (HR 3.0, 95% CI 1.1–7.8, P = 0.03). The evidence of a prognostic effect of AIB1 could be confirmed by linking gene expression data to outcome in independent publicly available ILC datasets. AR and GPER were neither associated to BCM with 10-year nor with 25-year FU (P > 0.33). Furthermore, Ki67 and NHG were prognostic for BCM at both 10-year and 25-year FU, whereas PR was not. Conclusions AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative ILC. Electronic supplementary material The online version of this article (10.1007/s10549-019-05138-7) contains supplementary material, which is available to authorized users.
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An Y, Adams JR, Hollern DP, Zhao A, Chang SG, Gams MS, Chung PED, He X, Jangra R, Shah JS, Yang J, Beck LA, Raghuram N, Kozma KJ, Loch AJ, Wang W, Fan C, Done SJ, Zacksenhaus E, Guidos CJ, Perou CM, Egan SE. Cdh1 and Pik3ca Mutations Cooperate to Induce Immune-Related Invasive Lobular Carcinoma of the Breast. Cell Rep 2018; 25:702-714.e6. [PMID: 30332649 PMCID: PMC6276789 DOI: 10.1016/j.celrep.2018.09.056] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/15/2018] [Accepted: 09/17/2018] [Indexed: 11/20/2022] Open
Abstract
CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1- and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators.
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Affiliation(s)
- Yeji An
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Jessica R Adams
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
| | - Daniel P Hollern
- Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Anthony Zhao
- Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Stephen G Chang
- Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Miki S Gams
- Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Philip E D Chung
- Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, and Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Xiaping He
- Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Rhea Jangra
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
| | - Juhi S Shah
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
| | - Joanna Yang
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
| | - Lauren A Beck
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
| | - Nandini Raghuram
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Katelyn J Kozma
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Amanda J Loch
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
| | - Wei Wang
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada
| | - Cheng Fan
- Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Susan J Done
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; The Campbell Family Institute for Breast Cancer Research at the Princess Margaret Cancer Centre and The Laboratory Medicine Program, University Health Network, Toronto, ON, Canada
| | - Eldad Zacksenhaus
- Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, and Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Cynthia J Guidos
- Program in Developmental and Stem Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Charles M Perou
- Lineberger Comprehensive Cancer Center, Departments of Genetics and Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
| | - Sean E Egan
- Program in Cell Biology, The Peter Gilgan Center for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G-0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
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Romero-Lorca A, Gaibar M, Armesilla AL, Fernandez-Santander A, Novillo A. Differential expression of PMCA2 mRNA isoforms in a cohort of Spanish patients with breast tumor types. Oncol Lett 2018; 16:6950-6959. [PMID: 30546427 PMCID: PMC6256341 DOI: 10.3892/ol.2018.9540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/29/2018] [Indexed: 01/01/2023] Open
Abstract
The present study examined the mRNA expression levels of different isoforms of the plasma membrane calcium ATPase 2 (PMCA2) gene generated by alternative splicing at the first intracellular loop (site A) and C-terminal region (site C) in 85 human breast cancer tumor and 69 adjacent non-tumor tissues. Associations were identified between the expression of PMCA2 splice isoforms and the following clinical variables: Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, tumor size, staging and histological classification, and lymph node status. Transcripts including splice site A or splice site C were amplified by reverse transcription-quantitative polymerase chain reaction using PMCA2 isoform-specific primers. Tumor and adjacent tissues were determined to express the different PMCA2 splice isoforms 2w, 2× and 2z (site A), and 2b (site C). The mRNA levels for these variants indicated high biological variability, but increased expression was observed in breast tumor tissues, compared with in adjacent tissues. Significantly increased PMCA2×/b expression levels were detected in breast tumor tissues histologically classified as lobulillar, compared with in ductal-types breast tumor tissues (P<0.028). Furthermore, PMCA2z expression was significantly associated with PR status (P<0.024, compared with in PR-negative tumor tissues), and PMCA2w expression was significantly associated with ER status (P<0.048, increased in ER-positive tumor tissues, compared with ER-negative tumor tissues). Finally, PMCA2b was overexpressed in HER2-positive tumor tissues, compared with in HER2-negative tumor tissues (P<0.014). The data demonstrated the differential mRNA expression of a number of splice site A and C variants of PMCA2 in breast tumor and adjacent tissues, depending on tumor hormone receptor status and histological classification. In agreement with previous data, PMCA2b was overexpressed in HER2-positive tumor tissues, indicating that high mRNA levels of this variant could be a marker of poor prognosis.
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Affiliation(s)
- Alicia Romero-Lorca
- Department of Basic Biomedical Sciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid 28670, Spain
| | - Maria Gaibar
- Department of Basic Biomedical Sciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid 28670, Spain
| | - Angel Luis Armesilla
- Faculty of Science and Engineering, School of Pharmacy, University of Wolverhampton, Wolverhampton, West Midlands WV1 1LY, UK
| | - Ana Fernandez-Santander
- Department of Basic Biomedical Sciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid 28670, Spain
| | - Apolonia Novillo
- Department of Basic Biomedical Sciences, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid 28670, Spain
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Chen Z, Yang J, Li S, Lv M, Shen Y, Wang B, Li P, Yi M, Zhao X, Zhang L, Wang L, Yang J. Invasive lobular carcinoma of the breast: A special histological type compared with invasive ductal carcinoma. PLoS One 2017; 12:e0182397. [PMID: 28863134 PMCID: PMC5580913 DOI: 10.1371/journal.pone.0182397] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 07/17/2017] [Indexed: 12/13/2022] Open
Abstract
The clinical outcomes and therapeutic strategies for infiltrating ductal carcinoma (IDC) and infiltrating lobular carcinoma (ILC) are not uniform. The primary objectives of this study were to identify the differences in the clinical characteristics and prognoses between ILC and IDC, and identify the high-risk population based on the hormone receptor status and metastasis sites. The Surveillance, Epidemiology, and End Results Program database was searched and patients diagnosed with ILC or IDC from 1990 to 2013 were identified. In total,796,335 patients were analyzed, including 85,048 withILC (10.7%) and 711,287 withIDC (89.3%). The ILC group was correlatedwith older age, larger tumor size, later stage, lower grade, metastasis disease(M1) disease, and greater counts ofpositive lymph nodesandestrogen-receptor-positive (ER)/progesterone receptor-positive (PR) positive nodes. The overall survival showed an early advantage for ILC but a worse outcome after 5 years. Regarding the disease-specific survival, the IDC cohort had advantages over the ILC group, both during the early years and long-term. In hormone status and metastasis site subgroup analyses, the ER+/PR+ subgroup had the best survival, while the ER+/PR- subgroup had the worst outcome, especially the ILC cohort. ILC and IDC had different metastasis patterns. The proportion of bone metastasis was higher in the ILC group (91.52%) than that in the IDC (76.04%), and the ILC group was more likely to have multiple metastasis sites. Survival analyses showed patients with ILC had a higher risk of liver metastasis (disease-specific survival[DSS]; P = 0.046), but had a better overall survival than the bone metastasis group (P<0.0001). We concluded that the long-term prognosis for ILC was poorer than that for IDC, and the ER+/PR- subgroup had the worst outcome. Therefore, the metastasis pattern and prognosis must be seriously evaluated, and a combination of endocrine therapy and chemotherapy should be considered.
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Affiliation(s)
- Zheling Chen
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Jiao Yang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Shuting Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Meng Lv
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Yanwei Shen
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Biyuan Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Pan Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Min Yi
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Xiao’ai Zhao
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Lingxiao Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Le Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Jin Yang
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
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Skvortsova II. Special issue: Progress in biological understanding of cancer metastasis. Semin Cancer Biol 2017; 44:1-2. [PMID: 28536032 DOI: 10.1016/j.semcancer.2017.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Ira-Ida Skvortsova
- Laboratory for Experimental and Translational Research on Radiation Oncology (EXTRO-Lab), Dept. of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Anichstr. 35, A-602 Innsbruck, Austria.
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