title: FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer.
abstract: Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
authors: Xiaoyong
authors: X
authors: Fu
authors: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Rinath
authors: R
authors: Jeselsohn
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
authors: Resel
authors: R
authors: Pereira
authors: Department of Pathology, Baylor College of Medicine, Houston, TX 77030.
authors: Emporia F
authors: EF
authors: Hollingsworth
authors: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors: Chad J
authors: CJ
authors: Creighton
authors: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Fugen
authors: F
authors: Li
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors: Martin
authors: M
authors: Shea
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors: Agostina
authors: A
authors: Nardone
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors: Carmine
authors: C
authors: De Angelis
authors: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239.
authors: Laura M
authors: LM
authors: Heiser
authors: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239.
authors: Pavana
authors: P
authors: Anur
authors: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239.
authors: Nicholas
authors: N
authors: Wang
authors: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239.
authors: Catherine S
authors: CS
authors: Grasso
authors: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239.
authors: Paul T
authors: PT
authors: Spellman
authors: McDonnell Genome Institute, Washington University, St. Louis, MO 63108.
authors: Obi L
authors: 0000-0002-0843-4271
authors: OL
authors: Griffith
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors: Anna
authors: A
authors: Tsimelzon
authors: Department of Pathology, Baylor College of Medicine, Houston, TX 77030.
authors: Carolina
authors: C
authors: Gutierrez
authors: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
authors: Shixia
authors: S
authors: Huang
authors: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Pathology, Baylor College of Medicine, Houston, TX 77030.
authors: Dean P
authors: DP
authors: Edwards
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Pharmacy Practice and Translational Research, University of Houston, Houston, TX 77204; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204.
authors: Meghana V
authors: MV
authors: Trivedi
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors: Mothaffar F
authors: MF
authors: Rimawi
authors: Department of Pathology, Baylor College of Medicine, Houston, TX 77030.
authors: Dolores
authors: D
authors: Lopez-Terrada
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors: Susan G
authors: SG
authors: Hilsenbeck
authors: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239.
authors: Joe W
authors: JW
authors: Gray
authors: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Myles
authors: M
authors: Brown
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030.
authors: C Kent
authors: CK
authors: Osborne
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030; rschiff@bcm.edu.
authors: Rachel
authors: R
authors: Schiff
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use; D059467:Transcriptome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D016209:Interleukin-8; D034741:RNA, Small Interfering; D013629:Tamoxifen
keywords: FOXA1; breast cancer; endocrine resistance; estrogen receptor; transcriptional reprogramming