A. A. MAAWY1, E. Katsuta1, L. Yan2, K. Takabe1 1Roswell Park Cancer Institute,Surgical Oncology,Buffalo, NY, USA 2Roswell Park Cancer Institute,Biostatistics And Bioinformatics,Buffalo, NY, USA
Introduction:
Bone morphogenetic proteins are members of the TGFβ family of signaling pathways and are known to be essential in fetal development, tissue differentiation and a multitude of cellular functions. Differential expression noted in some forms of breast cancer and is known to regulate the epithelial to mesenchymal transition, tissue infiltration and metastasis. Under-expression of BMP7 is known to be associated with a more metastatic phenotype and development of bone metastases. Studies in these patients have revealed aberrations of both BMP expression and signaling, which correlate clinically with disease progression. Identifying these tumor subsets can act as prognostic markers and may prove to be a therapeutic target with implications on disease progression and overall prognosis. This study investigates the association of BMP gene expression with breast cancer survival using a ‘big data’ approach employing RNA sequencing from the Cancer Genome Atlas (TCGA).
Methods:
A total of 1096 patient with breast cancer had treatment naïve samples of the tumors undergo genetic sequencing and the results of their sequencing stored in The Cancer Genome Atlas (TCGA) dataset. Overall survival (OS) was compared between high and low expression of indicated BMP related genes; BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP10, BMP15 and BMP receptors 1A and 1B, based upon RNA-sequencing data of TCGA.
Results:
The TCGA cohort was representative of national breast cancer patients with respect to stage, pathology and survival. Using Kaplan Meier analysis, BMP1 (p<0.001), BMP3 (p=0.002), BMP5 (p=0.02), BMP6 (p<0.001), BMP7 (p<0.001), BMP8a (p=0.054), BMP8b (p=0.001), BMPR1A (<0.001)and BMPR1B (p=0.005) all significantly impacted OS. BMP2, BMP4, BMP10 and BMP15 did not significantly impact OS. High expression of BMP1, BMP2, BMP3, BMP4, BMP5, BMP7 and BMPR1A was protective and was associated with improved OS. Conversely, high expression of BMP6, BMP8a, BMP8b and BMPR1B was associated with poorer outcomes and worse OS.
Conclusion:
BMP expression profiles may be of value in prognostication. Evidence suggests that BMPs play a role in breast tumorigenesis, function and progression by modulating the cell cycle, interactions with and remodeling of the extracellular matrix, interactions with the bone metastatic microenvironment and the epithelial to mesenchymal transition. Intervention in this pathway may serve to improve outcomes, manage metastatic disease and assist in clinical decision making on optimal therapy based on risk of recurrence or metastasis.