title: Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells.
abstract: Breast cancer (BC) is the leading cancer in women worldwide. Metastasis occurs in stage IV BC with bone and lung being common metastatic sites. Here we evaluate the effects of the aromatase inhibitor letrozole on BC micro-metastatic tumor growth in bone and lung metastasis in intact and ovariectomized (OVX) mice with murine estrogen receptor negative (ER-) BC cells inoculated in tibia. Forty-eight BALB/c mice were randomly assigned to one of four groups: OVX, OVX + Letrozole, Intact, and Intact + Letrozole, and injected with 4T1 cells intra-tibially. Letrozole was subcutaneously injected daily for 23 days at a dose of 1.75 µg/g body weight. Tumor progression was monitored by bioluminescence imaging (BLI). Following necropsy, inoculated tibiae were scanned via µCT and bone response to tumor was scored from 0 (no ectopic mineralization/osteolysis) to 5 (extensive ectopic mineralization/osteolysis). OVX mice had higher tibial pathology scores indicative of more extensive bone destruction than intact mice, irrespective of letrozole treatment. Letrozole decreased serum estradiol levels and reduced lung surface tumor numbers in intact animals. Furthermore, mice receiving letrozole had significantly fewer tumor colonies and fewer proliferative cells in the lung than OVX and intact controls based on H&E and Ki-67 staining, respectively. In conclusion, BC-inoculated OVX animals had higher tibia pathology scores than BC-inoculated intact animals and letrozole reduced BC metastases to lungs. These findings suggest that, by lowering systemic estrogen level and/or by interacting with the host organ, the aromatase inhibitor letrozole has the potential to reduce ER- BC metastasis to lung.
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 574 Bevier Hall, 905 South Goodwin Avenue, Urbana, IL, 61801, USA.
authors.forename: Wendan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 574 Bevier Hall, 905 South Goodwin Avenue, Urbana, IL, 61801, USA.
authors.forename: Aashvini
authors.initials: A
authors.lastname: Belosay
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 574 Bevier Hall, 905 South Goodwin Avenue, Urbana, IL, 61801, USA.
authors.forename: Xujuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 574 Bevier Hall, 905 South Goodwin Avenue, Urbana, IL, 61801, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Hartman
authors.affiliation: Health Sciences Center, School of Nursing, Texas Tech University, Lubbock, TX, USA.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Song
authors.affiliation: Skeletal Biology Laboratory, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR, USA.|Center for Healthy Aging Research, Oregon State University, Corvallis, OR, USA.
authors.forename: Urszula T
authors.initials: UT
authors.lastname: Iwaniec
authors.affiliation: Skeletal Biology Laboratory, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR, USA.|Center for Healthy Aging Research, Oregon State University, Corvallis, OR, USA.
authors.forename: Russell T
authors.initials: RT
authors.lastname: Turner
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Mona I
authors.initials: MI
authors.lastname: Churchwell
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 574 Bevier Hall, 905 South Goodwin Avenue, Urbana, IL, 61801, USA. helferic@illinois.edu.
authors.forename: William G
authors.identifier: 0000-0003-2697-7066
authors.initials: WG
authors.lastname: Helferich
mesh_terms: D000818:Animals; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D000077289:Letrozole; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D061206:Neoplasm Micrometastasis / Q000188:drug therapy* / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage*; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole
keywords: Aromatase inhibitor letrozole; Bioluminescence imaging; Breast cancer; Lung metastases; Micro-metastatic bone tumor; Ovariectomy; µCT