title: ERα-XPO1 Cross Talk Controls Tamoxifen Sensitivity in Tumors by Altering ERK5 Cellular Localization.
abstract: Most breast cancer deaths occur in women with recurrent, estrogen receptor (ER)-α(+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict the risk of endocrine therapy failure and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies. Using advanced statistical methods, we found that expression levels of several of nuclear transport genes including XPO1 were associated with poor survival and predicted recurrence of tamoxifen-treated breast tumors in human breast cancer gene expression data sets. In mechanistic studies we showed that the expression of XPO1 determined the cellular localization of the key signaling proteins and the response to tamoxifen. We demonstrated that combined targeting of XPO1 and ERα in several tamoxifen-resistant cell lines and tumor xenografts with the XPO1 inhibitor, Selinexor, and tamoxifen restored tamoxifen sensitivity and prevented recurrence in vivo. The nuclear transport pathways have not previously been implicated in the development of endocrine resistance, and given the need for better strategies for selecting patients to receive endocrine modulatory reagents and improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role these pathways play in reducing cancer recurrences.
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Kinga
authors.initials: K
authors.lastname: Wrobel
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Yiru Chen
authors.initials: YC
authors.lastname: Zhao
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Eylem
authors.initials: E
authors.lastname: Kulkoyluoglu
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Karen Lee Ann
authors.initials: KL
authors.lastname: Chen
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Kadriye
authors.initials: K
authors.lastname: Hieronymi
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Jamie
authors.initials: J
authors.lastname: Holloway
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Sarah
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Tania
authors.initials: T
authors.lastname: Ray
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Partha Sarathi
authors.initials: PS
authors.lastname: Ray
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Alexander Edward
authors.initials: AE
authors.lastname: Lipka
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Rebecca Lee
authors.initials: RL
authors.lastname: Smith
authors.affiliation: Department of Food Science and Human Nutrition (K.W., Y.C.Z., E.K., K.H., Z.M.-E.), Division of Nutritional Sciences (K.L.A.C., Z.M.-E.), University of Illinois at Urbana-Champaign, Departments of Surgery (P.S.R.) and Bioengineering (P.S.R.), Interdisciplinary Health Sciences Institute (P.S.R.), and Division of Surgical Oncology (P.S.R.), Carle Cancer Center, and Departments of Crop Sciences (A.E.L.) and Pathobiology (R.L.S.), College of Veterinary Medicine, Urbana, Illinois 61801; (J.H.), Arlington, Massachusetts; Onconostic Technologies Inc (S.L., T.R., P.S.R.), Urbana, Illinois 61820; Karyopharm Therapeutics (Y.L.), Newton, Massachusetts 02459; and Cancer Community Illinois (Z.M.-E.), Urbana, Illinois 61801.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Madak-Erdogan
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*; D000097606:Exportin 1 Protein
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D028884:Karyopherins; D048054:Mitogen-Activated Protein Kinase 7; D018160:Receptors, Cytoplasmic and Nuclear; D013629:Tamoxifen; D000097606:Exportin 1 Protein; C506487:ESR1 protein, human