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Published on: September 26, 2016
Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis
Milica Pavlovic1, Anna Arnal-Estapé1, Federico Rojo1
1Oncology Program (MP, AAE, AB, MT, MG, XGA, MM, JU, SG, RRG) and Biostatistics and Bioinformatics Unit (EP), Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Cancer Research Program (FR, AR, JA) and Microarray Analysis Service (LN), IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; Pathology Department, IIS-Fundación Jimenez Diaz, Madrid, Spain (FR); Medical Oncology Service, Hospital del Mar, Barcelona, Spain (AR, JA); Department of Oncology and Hematology, Hospital Clínico Universitario, Valencia, Spain (AL); Valencia Central University, Spain (AL); Inbiomotion, Barcelona, Spain (JJM); Sheffield Cancer Research Centre, Sheffield, UK (RC); Universitat Pompeu Fabra, Barcelona, Spain (JA); Translational Genomics, Vall d'Hebron Insitute of Oncology, Barcelona, Spain (AP); Department of Epidemiology, Harvard School of Public Health, Boston, MA (XGA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (RRG).
Background:
There are currently no biomarkers for early breast cancer patient populations at risk of bone metastasis. Identification of mediators of bone metastasis could be of clinical interest.
Methods:
A de novo unbiased screening approach based on selection of highly bone metastatic breast cancer cells in vivo was used to determine copy number aberrations (CNAs) associated with bone metastasis. The CNAs associated with bone metastasis were examined in independent primary breast cancer datasets with annotated clinical follow-up. The MAF gene encoded within the CNA associated with bone metastasis was subjected to gain and loss of function validation in breast cancer cells (MCF7, T47D, ZR-75, and 4T1), its downstream mechanism validated, and tested in clinical samples. A multivariable Cox cause-specific hazard model with competing events (death) was used to test the association between 16q23 or MAF and bone metastasis. All statistical tests were two-sided.
Results:
16q23 gain CNA encoding the transcription factor MAF mediates breast cancer bone metastasis through the control of PTHrP. 16q23 gain (hazard ratio (HR) for bone metastasis = 14.5, 95% confidence interval (CI) = 6.4 to 32.9, P < .001) as well as MAF overexpression (HR for bone metastasis = 2.5, 95% CI = 1.7 to 3.8, P < .001) in primary breast tumors were specifically associated with risk of metastasis to bone but not to other organs.
Conclusions:
These results suggest that MAF is a mediator of breast cancer bone metastasis. 16q23 gain or MAF protein overexpression in tumors may help to select patients at risk of bone relapse.
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