The effects of a novel hormonal breast cancer therapy, endoxifen, on the mouse skeleton.
Endoxifen has recently been identified as the predominant active metabolite of tamoxifen and is currently being developed as a novel hormonal therapy for the treatment of endocrine sensitive breast cancer. Based on past studies in breast cancer cells and model systems, endoxifen classically functions as an anti-estrogenic compound. Since estrogen and estrogen receptors play critical roles in mediating bone homeostasis, and endoxifen is currently being implemented as a novel breast cancer therapy, we sought to comprehensively characterize the in vivo effects of endoxifen on the mouse skeleton. Two month old ovariectomized C57BL/6 mice were treated with vehicle or 50 mg/kg/day endoxifen hydrochloride via oral gavage for 45 days. Animals were analyzed by dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, micro-computed tomography and histomorphometry. Serum from control and endoxifen treated mice was evaluated for bone resorption and bone formation markers. Gene expression changes were monitored in osteoblasts, osteoclasts and the cortical shells of long bones from endoxifen treated mice and in a human fetal osteoblast cell line. Endoxifen treatment led to significantly higher bone mineral density and bone mineral content throughout the skeleton relative to control animals. Endoxifen treatment also resulted in increased numbers of osteoblasts and osteoclasts per tissue area, which was corroborated by increased serum levels of bone formation and resorption markers. Finally, endoxifen induced the expression of osteoblast, osteoclast and osteocyte marker genes. These studies are the first to examine the in vivo and in vitro impacts of endoxifen on bone and our results demonstrate that endoxifen increases cancellous as well as cortical bone mass in ovariectomized mice, effects that may have implications for postmenopausal breast cancer patients.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
Anne
A
Gingery
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
Malayannan
M
Subramaniam
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
Kevin S
KS
Pitel
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America.
Jordan M
JM
Reese
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
Muzaffer
M
Cicek
Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America.
Laurence B
LB
Lindenmaier
Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States of America.
James N
JN
Ingle
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America; Department of Oncology, Mayo Clinic, Rochester, Minnesota, United States of America.
Matthew P
MP
Goetz
Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America.
Russell T
RT
Turner
Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, United States of America.
Urszula T
UT
Iwaniec
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
Thomas C
TC
Spelsberg
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
John R
JR
Hawse
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D001842:Bone and Bones / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D017931:DNA Primers; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D016133:Polymerase Chain Reaction; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D017931:DNA Primers; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen