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Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that include bone loss and its associated fracture. About half of the 391 patients treated with AIs in the Barcelona-Aromatase induced bone loss in early breast cancer cohort suffered a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on AI-treatment. In contrast, up to one-third (19.6% LS, 38.6% FN) showed no decline or even increased bone density. The present study aimed to determine the genetic basis for this variability. SNPs in candidate genes involved in vitamin D and estrogen hormone-response pathways (CYP11A1, CYP17A1, HSD3B2, HSD17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, DHCR7, GC, CYP2R1, CYP27B1, VDR and CYP24A1) were genotyped for association analysis with AI-related bone loss (AIBL). After multiple testing correction, 3 tag-SNPs (rs4077581, s11632698 and rs900798) located in the CYP11A1 gene were significantly associated (P<0.005) with FN AIBL at 2 years of treatment. Next, CYP11A1 expression in human fresh bone tissue and primary osteoblasts was demonstrated by RT-PCR. Both common isoforms of human cholesterol side-chain cleavage enzyme (encoded by CYP11A1 gene) were detected in osteoblasts by western blot. In conclusion, the genetic association of CYP11A1 gene with AIBL and its expression in bone tissue reveals a potential local function of this enzyme in bone metabolism regulation, offering a new vision of the steroidogenic ability of this tissue and new understanding of AI-induced bone loss.

Original publication

DOI

10.1530/jme-15-0079

Type

Journal article

Journal

Journal of molecular endocrinology

Publication Date

08/2015

Volume

55

Pages

69 - 79

Addresses

IMIM (Hospital del Mar Research Institute)Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF), ISCIII, Carrer del Doctor Aiguader 88, 08003 Barcelona, SpainInternal Medicine DepartmentHospital del Mar, Universitat Autònoma de Barcelona, Barcelona, SpainIDIAP Jordi Gol Primary Care Research InstituteUniversitat Autònoma de Barcelona, Barcelona, SpainNuffield Department of OrthopaedicsRheumatology and Musculoskeletal Sciences, Oxford NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UKMRC Lifecourse Epidemiology UnitUniversity of Southampton, Southampton, UKMedical Oncology DepartmentIMIM (Hospital del Mar Research Institute), Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, SpainDepartament de GenèticaUniversitat de Barcelona, IBUB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain.

Keywords

Bone and Bones, Osteoblasts, Humans, Breast Neoplasms, Osteoporosis, Postmenopausal, Cholesterol Side-Chain Cleavage Enzyme, Vitamin D, Aromatase Inhibitors, Estrogens, Bone Density, Genotype, Polymorphism, Single Nucleotide, Middle Aged, Female