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Matt R. Paul, … , Angela DeMichele, Lewis A. Chodosh
Published July 13, 2020
Citation Information: J Clin Invest. 2020;130(8):4252-4265. https://doi.org/10.1172/JCI129941.
Citation Information: J Clin Invest. 2020;130(8):4252-4265. https://doi.org/10.1172/JCI129941.
Abstract
Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. We performed whole-exome and shallow whole-genome sequencing to identify genes and pathways preferentially mutated or copy-number altered in metastases compared with the paired primary tumors from which they arose. Seven genes were preferentially mutated in metastases — MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1 — 5 of which are not significantly mutated in any type of human primary cancer. Four regions were preferentially copy-number altered: loss of STK11 and CDKN2A/B, as well as gain of PTK6 and the membrane-bound progesterone receptor, PAQR8. PAQR8 gain was mutually exclusive with mutations in the nuclear estrogen and progesterone receptors, suggesting a role in treatment resistance. Several pathways were preferentially mutated or altered in metastases, including mTOR, CDK/RB, cAMP/PKA, WNT, HKMT, and focal adhesion. Immunohistochemical analyses revealed that metastases preferentially inactivate pRB, upregulate the mTORC1 and WNT signaling pathways, and exhibit nuclear localization of activated PKA. Our findings identify multiple therapeutic targets in metastatic recurrence that are not significantly mutated in primary cancers, implicate membrane progesterone signaling and nuclear PKA in metastatic recurrence, and provide genomic bases for the efficacy of mTORC1, CDK4/6, and PARP inhibitors in metastatic breast cancer.
Authors
Matt R. Paul, Tien-chi Pan, Dhruv K. Pant, Natalie N.C. Shih, Yan Chen, Kyra L. Harvey, Aaron Solomon, David Lieberman, Jennifer J.D. Morrissette, Danielle Soucier-Ernst, Noah G. Goodman, S. William Stavropoulos, Kara N. Maxwell, Candace Clark, George K. Belka, Michael Feldman, Angela DeMichele, Lewis A. Chodosh
Citation information
Citations to this article (68)
| Title and authors | Publication | Year |
|---|---|---|
|
Role of immune cell homeostasis in research and treatment response in hepatocellular carcinoma
Song W, Li M, Liu W, Xu W, Zhou H, Wei S, Chi J |
Clinical and Experimental Medicine | 2025 |
|
Rare subclonal sequencing of breast cancers indicates putative metastatic driver mutations are predominately acquired after dissemination.
Lawrence-Paul MR, Pan TC, Pant DK, Shih NNC, Chen Y, Belka GK, Feldman M, DeMichele A, Chodosh LA |
Genome Medicine | 2024 |
|
Liver tropism of ER mutant breast cancer is characterized by unique molecular changes and immune infiltration.
Wu Y, Li Z, Lee AV, Oesterreich S, Luo B |
Breast Cancer Research and Treatment | 2024 |
|
Molecular alterations and prognosis of breast cancer with cutaneous metastasis
Xu Y, Ding L, Li C, Hua B, Wang S, Zhang J, Liu C, Guo R, Zhang Y |
Diagnostic Pathology | 2024 |
|
Serum Extracellular Vesicles Cargo Approach in Bitches with Mammary Tumors.
Sousa GC, Carvalho MG, Fonseca-Alves CE, Souza FF |
Current issues in molecular biology | 2024 |
|
Cancer, metastasis, and the epigenome.
Kiri S, Ryba T |
Molecular Cancer | 2024 |
|
Identification of Clinical Value and Biological Effects of XIRP2 Mutation in Hepatocellular Carcinoma
Li D, Bao X, Lei S, Cao W, Zeng Z, Chen T |
Biology | 2024 |
|
Deciphering breast cancer dynamics: insights from single-cell and spatial profiling in the multi-omics era.
Xiong X, Wang X, Liu CC, Shao ZM, Yu KD |
Biomarker research | 2024 |
|
High NTRK2 protein expression levels may be associated with poorer prognosis of breast cancer patients
Zhang R, Zhao J, Zhao L |
The Journal of International Medical Research | 2024 |
|
Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer
Herrera-Abreu MT, Guan J, Khalid U, Ning J, Costa MR, Chan J, Li Q, Fortin JP, Wong WR, Perampalam P, Biton A, Sandoval W, Vijay J, Hafner M, Cutts R, Wilson G, Frankum J, Roumeliotis TI, Alexander J, Hickman O, Brough R, Haider S, Choudhary J, Lord CJ, Swain A, Metcalfe C, Turner NC |
Nature Communications | 2024 |
|
Are the Common Genetic 3′UTR Variants in ADME Genes Playing a Role in Tolerance of Breast Cancer Chemotherapy?
Tęcza K, Kalinowska-Herok M, Rusinek D, Zajkowicz A, Pfeifer A, Oczko-Wojciechowska M, Pamuła-Piłat J |
International Journal of Molecular Sciences | 2024 |
|
Integration of clinical outcomes and molecular features in extramedullary disease in multiple myeloma
Nakamoto-Matsubara R, Nardi V, Horick N, Fukushima T, Han RS, Shome R, Ochi K, Panaroni C, Fulzele K, Rexha F, Branagan AR, Cirstea D, Yee AJ, Scadden DT, Raje NS |
Blood Cancer Journal | 2024 |
|
Distant Metastases of Breast Cancer Resemble Primary Tumors in Cancer Cell Composition but Differ in Immune Cell Phenotypes
Kuett L, Bollhagen A, Tietscher S, Sobottka B, Eling N, Varga Z, Moch H, de Souza N, Bodenmiller B |
Cancer Research | 2024 |
|
PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies
Chen S, Paul MR, Sterner CJ, Belka GK, Wang D, Xu P, Sreekumar A, Pan TC, Pant DK, Makhlin I, DeMichele A, Mesaros C, Chodosh LA |
Breast Cancer Research | 2023 |
|
Transcriptome Meta-Analysis of Triple-Negative Breast Cancer Response to Neoadjuvant Chemotherapy
Zhang W, Li E, Wang L, Lehmann BD, Chen XS |
Cancers | 2023 |
|
PAQR5 inhibits the growth and metastasis of clear cell renal cell carcinoma by suppressing the JAK/STAT3 signaling pathway.
Wang L, Yue Y, Zhang L, Jing M, Ma M, Liu C, Li Y, Xu S, Wang K, Wang X, Fan J, Zhang M |
Cellular oncology (Dordrecht) | 2023 |
|
Pathogenic variant profile in DNA damage response genes correlates with metastatic breast cancer progression-free survival in a Mexican-mestizo population
Vázquez-Romo R, Millan-Catalan O, Ruíz-García E, Martínez-Gutiérrez AD, Alvarado-Miranda A, Campos-Parra AD, López-Camarillo C, Jacobo-Herrera N, López-Urrutia E, Guardado-Estrada M, Cantú de León D, Pérez-Plasencia C |
Frontiers in Oncology | 2023 |
|
Characteristics of DNA macro-alterations in breast cancer with liver metastasis before treatment
Fan Y, Zou L, Zhong X, Wang Z, Wang Y, Luo C, Zheng H, Wang Y |
BMC Genomics | 2023 |
|
Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer
Jiang Z, Ju Y, Ali A, Chung PE, Skowron P, Wang DY, Shrestha M, Li H, Liu JC, Vorobieva I, Ghanbari-Azarnier R, Mwewa E, Koritzinsky M, Ben-David Y, Woodgett JR, Perou CM, Dupuy A, Bader GD, Egan SE, Taylor MD, Zacksenhaus E |
Nature Communications | 2023 |
|
Breast cancers as ecosystems: a metabolic perspective
Martino F, Lupi M, Giraudo E, Lanzetti L |
Cellular and Molecular Life Sciences | 2023 |
|
Organ-Specificity of Breast Cancer Metastasis
Ibragimova MK, Tsyganov MM, Kravtsova EA, Tsydenova IA, Litviakov NV |
International journal of molecular sciences | 2023 |
|
Prognostic impact of PTK6 expression in triple negative breast cancer
Chen Y, Qu W, Tu J, Yang L, Gui X |
BMC Women's Health | 2023 |
|
Fusing WGCNA and Machine Learning for Immune-Related Gene Prognostic Index in Lung Adenocarcinoma: Precision Prognosis, Tumor Microenvironment Profiling, and Biomarker Discovery
He J, Luan T, Zhao G, Yang Y |
Journal of inflammation research | 2023 |
|
Thinking (Metastasis) outside the (Primary Tumor) Box
Jiang Z, Ju YJ, Ali A, Chung PE, Wang DY, Liu JC, Li H, Vorobieva I, Mwewa E, Ghanbari-Azarnier R, Shrestha M, Ben-David Y, Zacksenhaus E |
Cancers | 2023 |
|
Regulation of mRNA translation by estrogen receptor in breast cancer.
Fard SS, Holz MK |
Steroids | 2023 |
|
Hotspot ESR1 Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis
Z Li, Y Wu, M Yates, N Tasdemir, A Bahreini, J Chen, K Levine, N Priedigkeit, A Nasrazadani, S Ali, L Buluwela, S Arnesen, J Gertz, J Richer, B Troness, D El-Ashry, Q Zhang, L Gerratana, Y Zhang, M Cristofanilli, M Montanez, P Sundd, C Wallace, S Watkins, C Fumagalli, E Guerini-Rocco, L Zhu, G Tseng, N Wagle, J Carroll, P Jank, C Denkert, M Karsten, J Blohmer, B Park, P Lucas, J Atkinson, A Lee, S Oesterreich |
Cancer research | 2022 |
|
Mutual exclusivity of ESR1 and TP53 mutations in endocrine resistant metastatic breast cancer
Z Li, N Spoelstra, M Sikora, S Sams, A Elias, J Richer, A Lee, S Oesterreich |
npj Breast Cancer | 2022 |
|
A genomic mutation spectrum of collecting duct carcinoma in the Chinese population
H Zhang, X Lu, G Huang, M Hua, W Zhang, T Wang, L Huang, Z Wang, Q Chen, J Li, Q Yang, G Yang |
BMC Medical Genomics | 2022 |
|
PAQR5 Expression Is Suppressed by TGFβ1 and Associated With a Poor Survival Outcome in Renal Clear Cell Carcinoma
C Tao, W Liu, X Yan, M Yang, S Yao, Q Shu, B Li, R Zhu |
Frontiers in Oncology | 2022 |
|
MED10 Drives the Oncogenicity and Refractory Phenotype of Bladder Urothelial Carcinoma Through the Upregulation of hsa-miR-590
C Wu, Y Wang, S Hu, W Wu, C Yeh, O Bamodu |
Frontiers in Oncology | 2022 |
|
PARP Inhibitors: A Major Therapeutic Option in Endocrine-Receptor Positive Breast Cancers
L Collet, J Péron, F Penault-Llorca, P Pujol, J Lopez, G Freyer, B You |
Cancers | 2022 |
|
Differences in the Molecular Profile between Primary Breast Carcinomas and Their Cutaneous Metastases
S González-Martínez, D Pizarro, B Pérez-Mies, T Caniego-Casas, J Rodríguez-Peralto, G Curigliano, A Cortés, M Gión, J Cortés, J Palacios |
Cancers | 2022 |
|
Extracellular Matrix-Based Gene Expression Signature Defines Two Prognostic Subtypes of Hepatocellular Carcinoma With Different Immune Microenvironment Characteristics
H Tang, T You, Z Sun, C Bai, Y Wang |
Frontiers in Molecular Biosciences | 2022 |
|
Comprehensive genome profiling by next generation sequencing of circulating tumor DNA in solid tumors: a single academic institution experience
V Caputo, V Falco, A Ventriglia, V Famiglietti, E Martinelli, F Morgillo, G Martini, C Corte, D Ciardiello, L Poliero, F Vita, M Orditura, M Fasano, R Franco, M Caraglia, A Avitabile, R Scalamogna, B Marchi, F Ciardiello, T Troiani, S Napolitano |
Therapeutic advances in medical oncology | 2022 |
|
Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer
Ruscitto F, Roda N, Priami C, Migliaccio E, Pelicci PG |
International journal of molecular sciences | 2022 |
|
Prediction of risk-associated genes and high-risk liver cancer patients from their mutation profile: benchmarking of mutation calling techniques
Patiyal S, Dhall A, Raghava GP |
2022 | |
|
Breast Cancer Genomics: Primary and Most Common Metastases
Bennett C, Carroll C, Wright C, Awad B, Park JM, Farmer M, Brown E(, Heatherly A, Woodard S |
Cancers | 2022 |
|
Investigating the shared genetic architecture of uterine leiomyoma and breast cancer: A genome-wide cross-trait analysis
Wu X, Xiao C, Han Z, Zhang L, Zhao X, Hao Y, Xiao J, Gallagher CS, Kraft P, Morton CC, Li J, Jiang X |
The American Journal of Human Genetics | 2022 |
|
Investigating the molecular mechanisms of Tamoxifen on the EMT pathway among patients with breast cancer.
Mirzaei M, Sheikholeslami SA, Jalili A, Bereimipour A, Sharbati S, Kaveh V, Salari S |
Journal of medicine and life | 2022 |
|
Breast cancer metastasis: Is it a matter of OMICS and proper ex-vivo models?
Cioce M, Sacconi A, Donzelli S, Bonomo C, Perracchio L, Carosi M, Telera S, Fazio VM, Botti C, Strano S, Blandino G |
Computational and Structural Biotechnology Journal | 2022 |
|
Comparison of dual mTORC1/2 inhibitor AZD8055 and mTORC1 inhibitor rapamycin on the metabolism of breast cancer cells using proton nuclear magnetic resonance spectroscopy metabolomics.
Ni Z, Xu S, Yu Z, Ye Z, Li R, Chen C, Yang J, Liu H, Zhou Z, Zhang X |
Investigational New Drugs | 2022 |
|
A Potential Anticancer Mechanism of Finger Root (Boesenbergia rotunda) Extracts against a Breast Cancer Cell Line
Widyananda MH, Wicaksono ST, Rahmawati K, Puspitarini S, Ulfa SM, Jatmiko YD, Masruri M, Widodo N |
Scientifica | 2022 |
|
The Multi-Omic Landscape of Primary Breast Tumors and Their Metastases: Expanding the Efficacy of Actionable Therapeutic Targets
Yang G, Lu T, Weisenberger DJ, Liang G |
Genes & development | 2022 |
|
Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers
Shah JB, Pueschl D, Wubbenhorst B, Fan M, Pluta J, D\u2019Andrea K, Hubert AP, Shilan JS, Zhou W, Kraya AA, Llop Guevara A, Ruan C, Serra V, Balmaña J, Feldman M, Morin PJ, Nayak A, Maxwell KN, Domchek SM, Nathanson KL |
Nature Communications | 2022 |
|
A new view of activating mutations in cancer
Nussinov R, Tsai CJ, Jang H |
Cancer research | 2022 |
|
Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis
Garcia-Recio S, Hinoue T, Wheeler GL, Kelly BJ, Garrido-Castro AC, Pascual T, De Cubas AA, Xia Y, Felsheim BM, McClure MB, Rajkovic A, Karaesmen E, Smith MA, Fan C, Ericsson PI, Sanders ME, Creighton CJ, Bowen J, Leraas K, Burns RT, Coppens S, Wheless A, Rezk S, Garrett AL, Parker JS, Foy KK, Shen H, Park BH, Krop I, Anders C, Gastier-Foster J, Rimawi MF, Nanda R, Lin NU, Isaacs C, Marcom PK, Storniolo AM, Couch FJ, Chandran U, Davis M, Silverstein J, Ropelewski A, Liu MC, Hilsenbeck SG, Norton L, Richardson AL, Symmans WF, Wolff AC, Davidson NE, Carey LA, Lee AV, Balko JM, Hoadley KA, Laird PW, Mardis ER, King TA, Perou CM |
2022 | |
|
Progression to Metastasis of Solid Cancer
E Zacksenhaus, SE Egan |
Cancers | 2021 |
|
WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer
K Menck, S Heinrichs, D Wlochowitz, M Sitte, H Noeding, A Janshoff, H Treiber, T Ruhwedel, B Schatlo, C von der Brelie, S Wiemann, T Pukrop, T Beißbarth, C Binder, A Bleckmann |
Journal of Experimental & Clinical Cancer Research | 2021 |
|
Tumour cell CD99 regulates transendothelial migration via CDC42 and actin remodelling
AJ Mannion, AF Odell, A Taylor, PF Jones, GP Cook |
Journal of cell science | 2021 |
|
Targeting mTOR and Glycolysis in HER2-Positive Breast Cancer
RW Holloway, PA Marignani |
Cancers | 2021 |
|
PARP and CDK4/6 Inhibitor Combination Therapy Induces Apoptosis and Suppresses Neuroendocrine Differentiation in Prostate Cancer
C Wu, S Peng, PG Pilié, C Geng, S Park, GC Manyam, Y Lu, G Yang, Z Tang, S Kondraganti, D Wang, CW Hudgens, DA Ledesma, ML Marques-Piubelli, CA Torres-Cabala, JL Curry, P Troncoso, PG Corn, BM Broom, TC Thompson |
Molecular cancer therapeutics | 2021 |
|
Genomic, Transcriptomic, and Proteomic Profiling of Metastatic Breast Cancer
A Akcakanat, X Zheng, CX Pico, TB Kim, K Chen, A Korkut, A Sahin, V Holla, E Tarco, G Singh, S Damodaran, GB Mills, AM Gonzalez-Angulo, F Meric-Bernstam |
Clinical cancer research | 2021 |
|
Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer
J Xie, EP Kusnadi, L Furic, LA Selth |
Cancers | 2021 |
|
Prognosis and Genomic Landscape of Liver Metastasis in Patients With Breast Cancer
C Tian, S Liu, Y Wang, X Song |
Frontiers in Oncology | 2021 |
|
SHOX2 cooperates with STAT3 to promote breast cancer metastasis through the transcriptional activation of WASF3
Y Teng, R Loveless, EM Benson, L Sun, AY Shull, C Shay |
Journal of Experimental & Clinical Cancer Research | 2021 |
|
miR-181a-2-3p Stimulates Gastric Cancer Progression via Targeting MYLK
J Li, X Xu, C Liu, , Y Wang, X Wu, H Li |
Frontiers in Bioengineering and Biotechnology | 2021 |
|
PAQR6 Upregulation Is Associated with AR Signaling and Unfavorite Prognosis in Prostate Cancers
M Yang, JC Li, C Tao, S Wu, B Liu, Q Shu, B Li, R Zhu |
Biomolecules | 2021 |
|
Clinical, Pathological, and Molecular Features of Breast Carcinoma Cutaneous Metastasis
S González-Martínez, D Pizarro, B Pérez-Mies, T Caniego-Casas, G Curigliano, J Cortés, J Palacios |
Cancers | 2021 |
|
Resistance to endocrine therapy in HR + and/or HER2 + breast cancer: the most promising predictive biomarkers
F Miranda, H Prazeres, F Mendes, D Martins, F Schmitt |
Molecular Biology Reports | 2021 |
|
Applications of Machine Learning to Predict Cisplatin Resistance in Lung Cancer
Y Gao, Q Lyu, P Luo, M Li, R Zhou, J Zhang, Q Lyu |
International journal of general medicine | 2021 |
|
Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes
N Ansari-Pour, Y Zheng, TF Yoshimatsu, A Sanni, M Ajani, JB Reynier, A Tapinos, JJ Pitt, S Dentro, A Woodard, PS Rajagopal, D Fitzgerald, AJ Gruber, A Odetunde, A Popoola, AG Falusi, CP Babalola, T Ogundiran, N Ibrahim, J Barretina, PV Loo, M Chen, KP White, O Ojengbede, J Obafunwa, D Huo, DC Wedge, OI Olopade |
Nature Communications | 2021 |
|
1H-NMR Plasma Lipoproteins Profile Analysis Reveals Lipid Metabolism Alterations in HER2-Positive Breast Cancer Patients
G Corona, ED Gregorio, A Vignoli, E Muraro, A Steffan, G Miolo |
Cancers | 2021 |
|
Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry
SP Gampenrieder, G Rinnerthaler, C Tinchon, A Petzer, M Balic, S Heibl, C Schmitt, AF Zabernigg, D Egle, M Sandholzer, CF Singer, F Roitner, C Hager, J Andel, M Hubalek, M Knauer, R Greil |
Breast Cancer Research | 2021 |
|
Complex roles of cAMP–PKA–CREB signaling in cancer
H Zhang, Q Kong, J Wang, Y Jiang, H Hua |
Experimental Hematology and Oncology | 2020 |
|
Genome-wide DNA methylation analysis of breast cancer MCF-7 / Taxol cells with MeDIP-Seq
Y Shi, W Gong, X Gong, P Wang, X Zhao, K Sossey-Alaoui |
PloS one | 2020 |
|
Targeting protein tyrosine kinase 6 in cancer
MB Gilic, AL Tyner |
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | 2020 |
|
Opportunities for Antigen Discovery in Metastatic Breast Cancer
AK Sood, M Nemeth, J Wang, Y Wu, S Gandhi |
Frontiers in immunology | 2020 |
|
Pulmonary immune responses against SARS-CoV-2 infection: harmful or not?
A Guillon, PS Hiemstra, M Si-Tahar |
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