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1. International survey on invasive lobular breast cancer identifies priority research questions

Author

Oesterreich, Steffi, Pate, Leigh, Lee, Adrian V, Chen, Fangyuan, Jankowitz, Rachel C, Mukhtar, Rita, Metzger, Otto, Sikora, Matthew J, Li, Christopher I, Sotiriou, Christos, Shah, Osama S, Koorman, Thijs, Ulaner, Gary, Reis-Filho, Jorge S, Davidson, Nancy M, Van Baelen, Karen, Hutcheson, Laurie, Freeney, Siobhan, Migyanka, Flora, Turner, Claire, Derksen, Patrick, Bear, Todd, and Desmedt, Christine

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Women's Health, Clinical Research, Cancer, Health Disparities, Breast Cancer, Clinical Trials and Supportive Activities, Clinical sciences, Oncology and carcinogenesis, Epidemiology
Abstract

There is growing awareness of the unique etiology, biology, and clinical presentation of invasive lobular breast cancer (ILC), but additional research is needed to ensure translation of findings into management and treatment guidelines. We conducted a survey with input from breast cancer physicians, laboratory-based researchers, and patients to analyze the current understanding of ILC, and identify consensus research questions. 1774 participants from 66 countries respondents self-identified as clinicians (N = 413), researchers (N = 376), and breast cancer patients and advocates (N = 1120), with some belonging to more than one category. The majority of physicians reported being very/extremely (41%) to moderately (42%) confident in describing the differences between ILC and invasive breast cancer of no special type (NST). Knowledge of histology was seen as important (73%) and as affecting treatment decisions (51%), and most agreed that refining treatment guidelines would be valuable (76%). 85% of clinicians have never powered a clinical trial to allow subset analysis for histological subtypes, but the majority would consider it, and would participate in an ILC clinical trials consortium. The majority of laboratory researchers, reported being and very/extremely (48%) to moderately (29%) confident in describing differences between ILC and NST. They reported that ILCs are inadequately presented in large genomic data sets, and that ILC models are insufficient. The majority have adequate access to tissue or blood from patients with ILC. The majority of patients and advocates (52%) thought that their health care providers did not sufficiently explain the unique features of ILC. They identified improvement of ILC screening/early detection, and identification of better imaging tools as top research priorities. In contrast, both researchers and clinicians identified understanding of endocrine resistance and identifying novel drugs that can be tested in clinical trials as top research priority. In summary, we have gathered information from an international community of physicians, researchers, and patients/advocates that we expect will lay the foundation for a community-informed collaborative research agenda, with the goal of improving management and personalizing treatment for patients with ILC.

Published
2024

11. Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer cell killing by DNA-directed therapies

Author

Hong, Lisa, Braden, Dennis C., Zhao, Yaoning, Skoko, John J., Chang, Fei, Woodcock, Steven R., Uvalle, Crystall, Casey, Allison, Wood, Katherine, Salvatore, Sonia R., Asan, Alparslan, Harkness, Trey, Fagunloye, Adeola, Razzaghi, Mortezaali, Straub, Adam, Spies, Maria, Brown, Daniel D., Lee, Adrian V., Schopfer, Francisco, Freeman, Bruce A., and Neumann, Carola A.

Published
2023
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13. Clinicopathologic and genomic features of lobular like invasive mammary carcinoma: is it a distinct entity?

Author

Yu, Jing, da Silva, Edaise M., La, Hae-Sun, Clark, Beth Z., Fine, Jeffrey L., Carter, Gloria J., Villatoro, Tatiana M., Soong, T. Rinda, Lee, Adrian V., Oesterreich, Steffi, Basili, Thais, Blanco-Heredia, Juan, Selenica, Pier, Ye, Qiqi, Da Cruz Paula, Arnaud, Dopeso, Higinio, Gazzo, Andrea, Marra, Antonio, Pareja, Fresia, Reis-Filho, Jorge S., and Bhargava, Rohit

Published
2023
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15. Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis

Author

Garcia-Recio, Susana, Hinoue, Toshinori, Wheeler, Gregory L., Kelly, Benjamin J., Garrido-Castro, Ana C., Pascual, Tomas, De Cubas, Aguirre A., Xia, Youli, Felsheim, Brooke M., McClure, Marni B., Rajkovic, Andrei, Karaesmen, Ezgi, Smith, Markia A., Fan, Cheng, Ericsson, Paula I. Gonzalez, Sanders, Melinda E., Creighton, Chad J., Bowen, Jay, Leraas, Kristen, Burns, Robyn T., Coppens, Sara, Wheless, Amy, Rezk, Salma, Garrett, Amy L., Parker, Joel S., Foy, Kelly K., Shen, Hui, Park, Ben H., Krop, Ian, Anders, Carey, Gastier-Foster, Julie, Rimawi, Mothaffar F., Nanda, Rita, Lin, Nancy U., Isaacs, Claudine, Marcom, P. Kelly, Storniolo, Anna Maria, Couch, Fergus J., Chandran, Uma, Davis, Michael, Silverstein, Jonathan, Ropelewski, Alexander, Liu, Minetta C., Hilsenbeck, Susan G., Norton, Larry, Richardson, Andrea L., Symmans, W. Fraser, Wolff, Antonio C., Davidson, Nancy E., Carey, Lisa A., Lee, Adrian V., Balko, Justin M., Hoadley, Katherine A., Laird, Peter W., Mardis, Elaine R., King, Tari A., and Perou, Charles M.

Published
2023
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17. Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas

Author

Müller, Sören, Agnihotri, Sameer, Shoger, Karsen E, Myers, Max I, Smith, Nicholas, Chaparala, Srilakshmi, Villanueva, Clarence R, Chattopadhyay, Ansuman, Lee, Adrian V, Butterfield, Lisa H, Diaz, Aaron, Okada, Hideho, Pollack, Ian F, and Kohanbash, Gary

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Immunotherapy, Brain Cancer, Immunization, Rare Diseases, Biotechnology, Clinical Research, Minority Health, Vaccine Related, Clinical Trials and Supportive Activities, Brain Disorders, Cancer, Pediatric, Neurosciences, 4.2 Evaluation of markers and technologies, 2.1 Biological and endogenous factors, 6.1 Pharmaceuticals, Good Health and Well Being, Adolescent, Adult, B7-H1 Antigen, Biomarkers, Tumor, Brain Neoplasms, Cancer Vaccines, Carboxymethylcellulose Sodium, Child, Follow-Up Studies, Glioma, Humans, Immunogenicity, Vaccine, Indoleamine-Pyrrole 2, 3, -Dioxygenase, Lymphocyte Activation, Male, Monocytes, Poly I-C, Polylysine, Progression-Free Survival, Sequence Analysis, RNA, Survival Analysis, T-Lymphocytes, Vaccines, Subunit, Young Adult, Cancer immunotherapy, Cellular immune response, Peptides, Vaccines, Biomedical and clinical sciences, Health sciences
Abstract

Low-grade gliomas (LGGs) are the most common brain tumor affecting children. We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points. Patients who showed CR demonstrated elevated levels of T cell activation markers, accompanied by a cytotoxic T cell response shortly after treatment initiation. At week 34, patients with CR demonstrated both IFN signaling and Poly-IC:LC adjuvant response patterns. Patients with PR demonstrated a unique, late monocyte response signature. Interestingly, HLA-V expression, before or during therapy, and an early monocytic hematopoietic response were strongly associated with SD. Finally, low IDO1 and PD-L1 expression before treatment and early elevated levels of T cell activation markers were associated with prolonged progression-free survival. Overall, our data support the presence of unique peripheral immune patterns in LGG patients associated with different radiographic responses to our peptide vaccine immunotherapy. Future clinical trials, including our ongoing phase II LGG vaccine immunotherapy, should monitor these response patterns.

Published
2018

18. An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

Author

Liu, Jianfang, Lichtenberg, Tara, Hoadley, Katherine A, Poisson, Laila M, Lazar, Alexander J, Cherniack, Andrew D, Kovatich, Albert J, Benz, Christopher C, Levine, Douglas A, Lee, Adrian V, Omberg, Larsson, Wolf, Denise M, Shriver, Craig D, Thorsson, Vesteinn, Network, The Cancer Genome Atlas Research, Caesar-Johnson, Samantha J, Demchok, John A, Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L, Hutter, Carolyn M, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C, Zhang, Jiashan, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I, Kim, Jaegil, Lawrence, Michael S, Lin, Pei, Meier, Sam, Noble, Michael S, Saksena, Gordon, Voet, Doug, Zhang, Hailei, Bernard, Brady, Chambwe, Nyasha, Dhankani, Varsha, Knijnenburg, Theo, Kramer, Roger, Leinonen, Kalle, Liu, Yuexin, Miller, Michael, Reynolds, Sheila, Shmulevich, Ilya, Zhang, Wei, Akbani, Rehan, Broom, Bradley M, Hegde, Apurva M, Ju, Zhenlin, Kanchi, Rupa S, Korkut, Anil, Li, Jun, Liang, Han, Ling, Shiyun, Liu, Wenbin, Lu, Yiling, Mills, Gordon B, Ng, Kwok-Shing, Rao, Arvind, Ryan, Michael, Wang, Jing, Weinstein, John N, Zhang, Jiexin, Abeshouse, Adam, Armenia, Joshua, Chakravarty, Debyani, Chatila, Walid K, de Bruijn, Ino, Gao, Jianjiong, Gross, Benjamin E, Heins, Zachary J, Kundra, Ritika, La, Konnor, Ladanyi, Marc, Luna, Augustin, Nissan, Moriah G, Ochoa, Angelica, Phillips, Sarah M, Reznik, Ed, Sanchez-Vega, Francisco, Sander, Chris, Schultz, Nikolaus, Sheridan, Robert, and Sumer, S Onur

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Genetics, Biotechnology, Cancer Genomics, Precision Medicine, Networking and Information Technology R&D (NITRD), Women's Health, Cancer, Good Health and Well Being, Databases, Genetic, Genomics, Humans, Kaplan-Meier Estimate, Neoplasms, Proportional Hazards Models, Cancer Genome Atlas Research Network, Cox proportional hazards regression model, TCGA, The Cancer Genome Atlas, clinical data resource, disease-free interval, disease-specific survival, follow-up time, overall survival, progression-free interval, translational research, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale.

Published
2018

21. Mapping molecular subtype specific alterations in breast cancer brain metastases identifies clinically relevant vulnerabilities

Author

Cosgrove, Nicola, Varešlija, Damir, Keelan, Stephen, Elangovan, Ashuvinee, Atkinson, Jennifer M., Cocchiglia, Sinéad, Bane, Fiona T., Singh, Vikrant, Furney, Simon, Hu, Chunling, Carter, Jodi M., Hart, Steven N., Yadav, Siddhartha, Goetz, Matthew P., Hill, Arnold D. K., Oesterreich, Steffi, Lee, Adrian V., Couch, Fergus J., and Young, Leonie S.

Published
2022
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22. ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

Author

Li, Zheqi, McGinn, Olivia, Wu, Yang, Bahreini, Amir, Priedigkeit, Nolan M., Ding, Kai, Onkar, Sayali, Lampenfeld, Caleb, Sartorius, Carol A., Miller, Lori, Rosenzweig, Margaret, Cohen, Ofir, Wagle, Nikhil, Richer, Jennifer K., Muller, William J., Buluwela, Laki, Ali, Simak, Bruno, Tullia C., Vignali, Dario A. A., Fang, Yusi, Zhu, Li, Tseng, George C., Gertz, Jason, Atkinson, Jennifer M., Lee, Adrian V., and Oesterreich, Steffi

Published
2022
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25. Mutual information for detecting multi-class biomarkers when integrating multiple bulk or single-cell transcriptomic studies.

Author

Zou, Jian, Li, Zheqi, Carleton, Neil, Oesterreich, Steffi, Lee, Adrian V, and Tseng, George C

Subjects
TRIPLE-negative breast cancer, TUMOR markers, FALSE discovery rate, STATISTICAL power analysis, TUMOR microenvironment
Abstract

Motivation Biomarker detection plays a pivotal role in biomedical research. Integrating omics studies from multiple cohorts can enhance statistical power, accuracy, and robustness of the detection results. However, existing methods for horizontally combining omics studies are mostly designed for two-class scenarios (e.g. cases versus controls) and are not directly applicable for studies with multi-class design (e.g. samples from multiple disease subtypes, treatments, tissues, or cell types). Results We propose a statistical framework, namely Mutual Information Concordance Analysis (MICA), to detect biomarkers with concordant multi-class expression pattern across multiple omics studies from an information theoretic perspective. Our approach first detects biomarkers with concordant multi-class patterns across partial or all of the omics studies using a global test by mutual information. A post hoc analysis is then performed for each detected biomarkers and identify studies with concordant pattern. Extensive simulations demonstrate improved accuracy and successful false discovery rate control of MICA compared to an existing multi-class correlation method. The method is then applied to two practical scenarios: four tissues of mouse metabolism-related transcriptomic studies, and three sources of estrogen treatment expression profiles. Detected biomarkers by MICA show intriguing biological insights and functional annotations. Additionally, we implemented MICA for single-cell RNA-Seq data for tumor progression biomarkers, highlighting critical roles of ribosomal function in the tumor microenvironment of triple-negative breast cancer and underscoring the potential of MICA for detecting novel therapeutic targets. Availability and implementation The source code is available on Figshare at https://doi.org/10.6084/m9.figshare.27635436. Additionally, the R package can be installed directly from GitHub at https://github.com/jianzou75/MICA. [ABSTRACT FROM AUTHOR]

Published
2024
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26. Cancer-cell derived S100A11 promotes macrophage recruitment in ER+ breast cancer.

Author

Lee, Sanghoon, Cho, Youngbin, Li, Yiting, Li, Ruxuan, Lau, Angela Wong, Laird, Matthew S., Brown, Daniel, McAuliffe, Priscilla, Lee, Adrian V., Oesterreich, Steffi, Zervantonakis, Ioannis K., and Osmanbeyoglu, Hatice Ulku

Subjects
GENE silencing, CANCER cells, EPITHELIAL cells, BREAST tumors, TUMOR microenvironment
Abstract

Macrophages are pivotal in driving breast tumor development, progression, and resistance to treatment, particularly in estrogen receptor-positive (ER+) tumors, where they infiltrate the tumor microenvironment (TME) influenced by cancer cell-secreted factors. By analyzing single-cell RNA sequencing data from 25 ER+ tumors, we elucidated interactions between cancer cells and macrophages, correlating macrophage density with epithelial cancer cell density. We identified that S100A11, a previously unexplored factor in macrophage-cancer crosstalk, predicts high macrophage density and poor outcomes in ER+ tumors. We found that recombinant S100A11 enhances macrophage infiltration and migration in a dose-dependent manner. Additionally, in a 3D matrix using a panel of three ER+ breast cancer cell lines, we showed that secreted S100A11 levels from cancer cells were associated with increased monocyte infiltration that subsequently differentiation toward macrophages. Genetic silencing of S100A11 in the S100A11-high T47D cancer cells reduced monocyte infiltration, consistent with results using a S100A11 blocking antibody in T47D cancer cells and in a clinically relevant patient-derived organoid model. Phenotypic analysis of macrophages cocultured with T47D cancer cells following S100A11 knockdown revealed lower expression of the immunosuppressive marker CD206, further underscoring the role of S100A11 as a paracrine regulator of pro-tumorigenic cancer-macrophage crosstalk. This study offers novel insights into the interplay between macrophages and cancer cells in ER+ breast tumors, highlighting S100A11 as a potential therapeutic target to modulate the macrophage-rich tumor microenvironment. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Electronic Health Record–Based Nudge Intervention and Axillary Surgery in Older Women With Breast Cancer: A Nonrandomized Controlled Trial.

Author

Carleton, Neil, Radomski, Thomas R., Li, Danyang, Zou, Jian, Harris, John, Hamm, Megan, Wang, Ziqi, Saadawi, Gilan, Fischer, Gary S., Arnold, Jonathan, Cowher, Michael S., Lupinacci, Kristin, Sabih, Quratulain, Steiman, Jennifer, Johnson, Ronald R., Soran, Atilla, Diego, Emilia J., Oesterreich, Steffi, Tseng, George, and Lee, Adrian V.

Published
2024
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28. ESR1 Fusions Invoke Breast Cancer Subtype-Dependent Enrichment of Ligand-Independent Oncogenic Signatures and Phenotypes.

Author

Yates, Megan E, Waltermire, Hunter, Mori, Kanako, Li, Zheqi, Li, Yiting, Guzolik, Hannah, Wang, Xiaosong, Liu, Tiantong, Atkinson, Jennifer M, Hooda, Jagmohan, Lee, Adrian V, and Oesterreich, Steffi

Subjects
ESTROGEN receptors, LOBULAR carcinoma, BREAST cancer, CELL lines, DUCTAL carcinoma, METASTATIC breast cancer
Abstract

Breast cancer is a leading cause of female mortality and despite advancements in personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. The estrogen receptor (ER, ESR1) is expressed in two-thirds of all breast cancer, and under endocrine stress, somatic ESR1 mutations arise in approximately 30% of cases that result in endocrine resistance. We and others reported ESR1 fusions as a mechanism of ER-mediated endocrine resistance. ER fusions, which retain the activation function 1- and DNA-binding domains, harbor ESR1 exons 1 to 6 fused to an in-frame gene partner resulting in loss of the ER ligand-binding domain (LBD). We demonstrate that in a no-special type (invasive ductal carcinoma [IDC]-NST) and an invasive lobular carcinoma (ILC) cell line, ER fusions exhibit robust hyperactivation of canonical ER signaling pathways independent of estradiol or antiendocrine therapies. We employ cell line models stably overexpressing ER fusions with concurrent endogenous ER knockdown to minimize endogenous ER influence. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably MYC signaling. Cells expressing the 3′ fusion partners SOX9 and YAP1 consistently demonstrated enhanced growth and cell survival. ILC cells expressing the DAB2 fusion led to enhanced growth, survival, and migration, phenotypes not appreciated in the IDC-NST DAB2 model. Herein, we report that cell line activity is subtype-, fusion-, and assay-specific, suggesting that LBD loss, the fusion partner, and the cellular landscape all influence fusion activities. Therefore, it will be critical to assess fusion frequency in the context of the clinicopathology. [ABSTRACT FROM AUTHOR]

Published
2024
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29. Publisher Correction: Immune landscape in invasive ductal and lobular breast cancer reveals a divergent macrophage-driven microenvironment

Author

Onkar, Sayali, Cui, Jian, Zou, Jian, Cardello, Carly, Cillo, Anthony R., Uddin, Mostofa Rafid, Sagan, April, Joy, Marion, Osmanbeyoglu, Hatice U., Pogue-Geile, Katherine L., McAuliffe, Priscilla F., Lucas, Peter C., Tseng, George C., Lee, Adrian V., Bruno, Tullia C., Oesterreich, Steffi, and Vignali, Dario A. A.

Published
2023
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32. Comparative analysis of the AIB1 interactome in breast cancer reveals MTA2 as a repressive partner which silences E-Cadherin to promote EMT and associates with a pro-metastatic phenotype

Author

Varešlija, Damir, Ward, Elspeth, Purcell, Siobhan P., Cosgrove, Nicola S., Cocchiglia, Sinéad, O’Halloran, Philip J., Charmsaz, Sara, Bane, Fiona T., Brett, Francesca M., Farrell, Michael, Cryan, Jane, Beausang, Alan, Hudson, Lance, Turnbul, Arran K., Dixon, J. Michael, Hill, Arnold D. K., Priedigkeit, Nolan, Oesterreich, Steffi, Lee, Adrian V., Sims, Andrew H., Redmond, Aisling M., Carroll, Jason S., and Young, Leonie S.

Published
2021
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33. International survey on invasive lobular breast cancer identifies priority research questions

Author

Pathologie patiënten zorg, Pathologie Groep Derksen, Cancer, Oesterreich, Steffi, Pate, Leigh, Lee, Adrian V., Chen, Fangyuan, Jankowitz, Rachel C., Mukhtar, Rita, Metzger, Otto, Sikora, Matthew J., Li, Christopher I., Sotiriou, Christos, Shah, Osama S., Koorman, Thijs, Ulaner, Gary, Reis-Filho, Jorge S., Davidson, Nancy M., Van Baelen, Karen, Hutcheson, Laurie, Freeney, Siobhan, Migyanka, Flora, Turner, Claire, Derksen, Patrick, Bear, Todd, Desmedt, Christine, Pathologie patiënten zorg, Pathologie Groep Derksen, Cancer, Oesterreich, Steffi, Pate, Leigh, Lee, Adrian V., Chen, Fangyuan, Jankowitz, Rachel C., Mukhtar, Rita, Metzger, Otto, Sikora, Matthew J., Li, Christopher I., Sotiriou, Christos, Shah, Osama S., Koorman, Thijs, Ulaner, Gary, Reis-Filho, Jorge S., Davidson, Nancy M., Van Baelen, Karen, Hutcheson, Laurie, Freeney, Siobhan, Migyanka, Flora, Turner, Claire, Derksen, Patrick, Bear, Todd, and Desmedt, Christine

Published
2024

34. Phylogenies Derived from Matched Transcriptome Reveal the Evolution of Cell Populations and Temporal Order of Perturbed Pathways in Breast Cancer Brain Metastases

Author

Tao, Yifeng, Lei, Haoyun, Lee, Adrian V., Ma, Jian, Schwartz, Russell, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Woeginger, Gerhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Bebis, George, editor, Benos, Takis, editor, Chen, Ken, editor, Jahn, Katharina, editor, and Lima, Ernesto, editor

Published
2019
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36. Research autopsy programmes in oncology: shared experience from 14 centres across the world

Author

Geukens, Tatjana, primary, Maetens, Marion, additional, Hooper, Jody E, additional, Oesterreich, Steffi, additional, Lee, Adrian V, additional, Miller, Lori, additional, Atkinson, Jenny M, additional, Rosenzweig, Margaret, additional, Puhalla, Shannon, additional, Thorne, Heather, additional, Devereux, Lisa, additional, Bowtell, David, additional, Loi, Sherene, additional, Bacon, Eliza R, additional, Ihle, Kena, additional, Song, Mihae, additional, Rodriguez‐Rodriguez, Lorna, additional, Welm, Alana L, additional, Gauchay, Lisa, additional, Murali, Rajmohan, additional, Chanda, Pharto, additional, Karacay, Ali, additional, Naceur‐Lombardelli, Cristina, additional, Bridger, Hayley, additional, Swanton, Charles, additional, Jamal‐Hanjani, Mariam, additional, Kollath, Lori, additional, True, Lawrence, additional, Morrissey, Colm, additional, Chambers, Meagan, additional, Chinnaiyan, Arul M, additional, Wilson, Allecia, additional, Mehra, Rohit, additional, Reichert, Zachery, additional, Carey, Lisa A, additional, Perou, Charles M, additional, Kelly, Erin, additional, Maeda, Daichi, additional, Goto, Akiteru, additional, Kulka, Janina, additional, Székely, Borbála, additional, Szasz, A Marcell, additional, Tőkés, Anna‐Mária, additional, Van Den Bogaert, Wouter, additional, Floris, Giuseppe, additional, and Desmedt, Christine, additional

Published
2024
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42. Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.

Author

Shah, Osama Shiraz, Nasrazadani, Azadeh, Foldi, Julia, Atkinson, Jennifer M., Kleer, Celina G., McAuliffe, Priscilla F., Johnston, Tyler J., Stallaert, Wayne, da Silva, Edaise M., Selenica, Pier, Dopeso, Higinio, Pareja, Fresia, Mandelker, Diana, Weigelt, Britta, Reis-Filho, Jorge S., Bhargava, Rohit, Lucas, Peter C., Lee, Adrian V., and Oesterreich, Steffi

Subjects
TRIPLE-negative breast cancer, LOBULAR carcinoma, ESTROGEN receptors, BREAST cancer, DUCTAL carcinoma
Abstract

Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity - e.g., MDLC with triple-negative breast cancer (TNBC) or basal ductal and estrogen receptor positive (ER+) luminal lobular regions, distinct enrichment of cell cycle arrest/senescence and oncogenic (ER and MYC) signatures, genetic and epigenetic CDH1 inactivation in lobular but not ductal regions, and single-cell ductal and lobular subpopulations with unique oncogenic signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that the intratumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma. [ABSTRACT FROM AUTHOR]

Published
2024
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44. An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

Author

Caesar-Johnson, Samantha J., Demchok, John A., Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L., Hutter, Carolyn M., Sofia, Heidi J., Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C., Zhang, Jiashan (Julia), Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I., Kim, Jaegil, Lawrence, Michael S., Lin, Pei, Meier, Sam, Noble, Michael S., Saksena, Gordon, Voet, Doug, Zhang, Hailei, Bernard, Brady, Chambwe, Nyasha, Dhankani, Varsha, Knijnenburg, Theo, Kramer, Roger, Leinonen, Kalle, Liu, Yuexin, Miller, Michael, Reynolds, Sheila, Shmulevich, Ilya, Thorsson, Vesteinn, Zhang, Wei, Akbani, Rehan, Broom, Bradley M., Hegde, Apurva M., Ju, Zhenlin, Kanchi, Rupa S., Korkut, Anil, Li, Jun, Liang, Han, Ling, Shiyun, Liu, Wenbin, Lu, Yiling, Mills, Gordon B., Ng, Kwok-Shing, Rao, Arvind, Ryan, Michael, Wang, Jing, Weinstein, John N., Zhang, Jiexin, Abeshouse, Adam, Armenia, Joshua, Chakravarty, Debyani, Chatila, Walid K., de Bruijn, Ino, Gao, Jianjiong, Gross, Benjamin E., Heins, Zachary J., Kundra, Ritika, La, Konnor, Ladanyi, Marc, Luna, Augustin, Nissan, Moriah G., Ochoa, Angelica, Phillips, Sarah M., Reznik, Ed, Sanchez-Vega, Francisco, Sander, Chris, Schultz, Nikolaus, Sheridan, Robert, Sumer, S. Onur, Sun, Yichao, Taylor, Barry S., Wang, Jioajiao, Zhang, Hongxin, Anur, Pavana, Peto, Myron, Spellman, Paul, Benz, Christopher, Stuart, Joshua M., Wong, Christopher K., Yau, Christina, Hayes, D. Neil, Parker, Joel S., Wilkerson, Matthew D., Ally, Adrian, Balasundaram, Miruna, Bowlby, Reanne, Brooks, Denise, Carlsen, Rebecca, Chuah, Eric, Dhalla, Noreen, Holt, Robert, Jones, Steven J.M., Kasaian, Katayoon, Lee, Darlene, Ma, Yussanne, Marra, Marco A., Mayo, Michael, Moore, Richard A., Mungall, Andrew J., Mungall, Karen, Robertson, A. Gordon, Sadeghi, Sara, Schein, Jacqueline E., Sipahimalani, Payal, Tam, Angela, Thiessen, Nina, Tse, Kane, Wong, Tina, Berger, Ashton C., Beroukhim, Rameen, Cherniack, Andrew D., Cibulskis, Carrie, Gabriel, Stacey B., Gao, Galen F., Ha, Gavin, Meyerson, Matthew, Schumacher, Steven E., Shih, Juliann, Kucherlapati, Melanie H., Kucherlapati, Raju S., Baylin, Stephen, Cope, Leslie, Danilova, Ludmila, Bootwalla, Moiz S., Lai, Phillip H., Maglinte, Dennis T., Van Den Berg, David J., Weisenberger, Daniel J., Auman, J. 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Houston, Torbenson, Michael, Yang, Ju Dong, Zhang, Lizhi, Brimo, Fadi, Ajani, Jaffer A., Angulo Gonzalez, Ana Maria, Behrens, Carmen, Bondaruk, Jolanta, Broaddus, Russell, Czerniak, Bogdan, Esmaeli, Bita, Fujimoto, Junya, Gershenwald, Jeffrey, Guo, Charles, Lazar, Alexander J., Logothetis, Christopher, Meric-Bernstam, Funda, Moran, Cesar, Ramondetta, Lois, Rice, David, Sood, Anil, Tamboli, Pheroze, Thompson, Timothy, Troncoso, Patricia, Tsao, Anne, Wistuba, Ignacio, Carter, Candace, Haydu, Lauren, Hersey, Peter, Jakrot, Valerie, Kakavand, Hojabr, Kefford, Richard, Lee, Kenneth, Long, Georgina, Mann, Graham, Quinn, Michael, Saw, Robyn, Scolyer, Richard, Shannon, Kerwin, Spillane, Andrew, Stretch, Jonathan, Synott, Maria, Thompson, John, Wilmott, James, Al-Ahmadie, Hikmat, Chan, Timothy A., Ghossein, Ronald, Gopalan, Anuradha, Levine, Douglas A., Reuter, Victor, Singer, Samuel, Singh, Bhuvanesh, Tien, Nguyen Viet, Broudy, Thomas, Mirsaidi, Cyrus, Nair, Praveen, Drwiega, Paul, Miller, Judy, Smith, Jennifer, Zaren, Howard, Park, Joong-Won, Hung, Nguyen Phi, Kebebew, Electron, Linehan, W. Marston, Metwalli, Adam R., Pacak, Karel, Pinto, Peter A., Schiffman, Mark, Schmidt, Laura S., Vocke, Cathy D., Wentzensen, Nicolas, Worrell, Robert, Yang, Hannah, Moncrieff, Marc, Goparaju, Chandra, Melamed, Jonathan, Pass, Harvey, Botnariuc, Natalia, Caraman, Irina, Cernat, Mircea, Chemencedji, Inga, Clipca, Adrian, Doruc, Serghei, Gorincioi, Ghenadie, Mura, Sergiu, Pirtac, Maria, Stancul, Irina, Tcaciuc, Diana, Albert, Monique, Alexopoulou, Iakovina, Arnaout, Angel, Bartlett, John, Engel, Jay, Gilbert, Sebastien, Parfitt, Jeremy, Sekhon, Harman, Thomas, George, Rassl, Doris M., Rintoul, Robert C., Bifulco, Carlo, Tamakawa, Raina, Urba, Walter, Hayward, Nicholas, Timmers, Henri, Antenucci, Anna, Facciolo, Francesco, Grazi, Gianluca, Marino, Mirella, Merola, Roberta, de Krijger, Ronald, Gimenez-Roqueplo, Anne-Paule, Piché, Alain, Chevalier, Simone, McKercher, Ginette, Birsoy, Kivanc, Barnett, Gene, Brewer, Cathy, Farver, Carol, Naska, Theresa, Pennell, Nathan A., Raymond, Daniel, Schilero, Cathy, Smolenski, Kathy, Williams, Felicia, Morrison, Carl, Borgia, Jeffrey A., Liptay, Michael J., Pool, Mark, Seder, Christopher W., Junker, Kerstin, Omberg, Larsson, Dinkin, Mikhail, Manikhas, George, Alvaro, Domenico, Bragazzi, Maria Consiglia, Cardinale, Vincenzo, Carpino, Guido, Gaudio, Eugenio, Chesla, David, Cottingham, Sandra, Dubina, Michael, Moiseenko, Fedor, Dhanasekaran, Renumathy, Becker, Karl-Friedrich, Janssen, Klaus-Peter, Slotta-Huspenina, Julia, Abdel-Rahman, Mohamed H., Aziz, Dina, Bell, Sue, Cebulla, Colleen M., Davis, Amy, Duell, Rebecca, Elder, J. 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Kimryn, Fantacone-Campbell, J. Leigh, Hooke, Jeffrey A., Kovatich, Albert J., Shriver, Craig D., DiPersio, John, Drake, Bettina, Govindan, Ramaswamy, Heath, Sharon, Ley, Timothy, Van Tine, Brian, Westervelt, Peter, Rubin, Mark A., Lee, Jung Il, Aredes, Natália D., Mariamidze, Armaz, Liu, Jianfang, Lichtenberg, Tara, Poisson, Laila M., Benz, Christopher C., Lee, Adrian V., and Wolf, Denise M.

Published
2018
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46. A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

Author

Dearth, Robert K, Kuiatse, Isere, Wang, Yu-Fen, Liao, Lan, Hilsenbeck, Susan G, Brown, Powel H, Xu, Jianming, and Lee, Adrian V

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Cell Transformation, Neoplastic, Female, Gene Expression Regulation, Insulin-Like Growth Factor I, Mammary Glands, Animal, Mammary Neoplasms, Experimental, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptor, ErbB-2, Signal Transduction, Transgenes, Receptor, erbB-2, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Epidemiology
Abstract

BackgroundEpidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth.MethodsWe crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm(3). For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice.ResultsTTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands.ConclusionUsing the first transgenic animal model to elevate circulating levels of IGF-I to those comparable to women at increased risk of breast cancer, we showed that moderately high levels of systemic IGF-I have no effect on pubertal mammary gland development, initiating mammary tumorigenesis or promoting ErbB2 driven mammary carcinogenesis. Our work suggests that ErbB2-induced mammary tumorigenesis is independent of the normal variation in circulating levels of IGF-I.

Published
2011

47. Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen receptor (ER) levels and activity in ER+ breast cancer

Author

Creighton, Chad J, Fu, Xiaoyong, Hennessy, Bryan T, Casa, Angelo J, Zhang, Yiqun, Gonzalez-Angulo, Ana Maria, Lluch, Ana, Gray, Joe W, Brown, Powell H, Hilsenbeck, Susan G, Osborne, C Kent, Mills, Gordon B, Lee, Adrian V, and Schiff, Rachel

Abstract

Abstract Introduction Accumulating evidence suggests that both levels and activity of the estrogen receptor (ER) and the progesterone receptor (PR) are dramatically influenced by growth-factor receptor (GFR) signaling pathways, and that this crosstalk is a major determinant of both breast cancer progression and response to therapy. The phosphatidylinositol 3-kinase (PI3K) pathway, a key mediator of GFR signaling, is one of the most altered pathways in breast cancer. We thus examined whether deregulated PI3K signaling in luminal ER+ breast tumors is associated with ER level and activity and intrinsic molecular subtype. Methods We defined two independent molecular signatures of the PI3K pathway: a proteomic (reverse-phase proteomic array) PI3K signature, based on protein measurement for PI3K signaling intermediates, and a PI3K transcriptional (mRNA) signature based on the set of genes either induced or repressed by PI3K inhibitors. By using these signatures, we scored each ER+ breast tumor represented in multiple independent expression-profiling datasets (four mRNA, n = 915; one protein, n = 429) for activation of the PI3K pathway. Effects of PI3K inhibitor BEZ-235 on ER expression and activity levels and cell growth were tested by quantitative real-time PCR and cell proliferation assays. Results Within ER+ tumors, ER levels were negatively correlated with the PI3K activation scores, both at the proteomic and transcriptional levels, in all datasets examined. PI3K signature scores were also higher in ER+ tumors and cell lines of the more aggressive luminal B molecular subtype versus those of the less aggressive luminal A subtype. Notably, BEZ-235 treatment in four different ER+ cell lines increased expression of ER and ER target genes including PR, and treatment with IGF-I (which signals via PI3K) decreased expression of ER and target genes, thus further establishing an inverse functional relation between ER and PI3K. BEZ-235 had an additional effect on tamoxifen in inhibiting the growth of a number of ER+ cell lines. Conclusions Our data suggest that luminal B tumors have hyperactive GFR/PI3K signaling associated with lower ER levels, which has been correlated with resistance to endocrine therapy. Targeting PI3K in these tumors might reverse loss of ER expression and signaling and restore hormonal sensitivity.

Published
2010

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