Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis.

Abstract

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.

• Authors: Milica Pavlovic, Anna Arnal-Estapé, Federico Rojo, Anna Bellmunt, Maria Tarragona, Marc Guiu, Evarist Planet, Xabier Garcia-Albéniz, Mónica Morales, Jelena Urosevic, Sylwia Gawrzak, Ana Rovira, Aleix Prat, Lara Nonell, Ana Lluch, Joël Jean-Mairet, Robert Coleman, Joan Albanell, Roger R Gomis
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 107 Issue 12 Pg. djv256 (Dec 2015) ISSN: 1460-2105 [Electronic] United States
• PMID: 26376684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press.

Chemical References

• Biomarkers, Tumor
• MAF protein, human
• Proto-Oncogene Proteins c-maf

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Bone Neoplasms (metabolism, secondary)
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• DNA Copy Number Variations
• Female
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Incidence
• Mice
• Mice, Inbred BALB C
• Odds Ratio
• Predictive Value of Tests
• Prognosis
• Proportional Hazards Models
• Proto-Oncogene Proteins c-maf (metabolism)
• Up-Regulation