Vanderbilt-Ingram Cancer Center researchers have uncovered a gene signature that may help predict clinical outcomes in certain types of breast cancer.
In the Journal of Clinical Investigation, Harold (Hal) Moses, M.D., and colleagues report that this gene signature – which is associated with the transforming growth factor-beta (TGF-β) signaling pathway – correlates with reduced relapse-free survival in patients with breast cancer, especially in those with estrogen receptor (ER) positive tumors.
The results suggest that assessing TGF-β signaling may be a useful aid in determining breast cancer prognosis and in guiding treatment. The work also sheds light on how TGF-β affects tumor growth and progression.
TGF-β is a well-known regulator of tumor growth and metastasis. In the early stages of cancer, TGF-β signaling inhibits tumor growth. But for unclear reasons, most tumors eventually lose their sensitivity to TGF-β, and the once-beneficial protein begins promoting tumor growth and metastasis during later cancer stages. Loss of TGF-β signaling has been linked to tumor progression in human breast cancer.
To identify mechanisms by which TGF-β regulates tumor progression and metastasis, Brian Bierie, Ph.D., a former graduate student in the Moses lab, developed mammary cancer cell lines from mice lacking the TGF-β type II receptor (TβRII), an important component of the TGF-β signaling pathway.
Bierie examined gene expression in these cell lines and found that TGF-β signaling regulates the expression of chemokines, inflammation-associated chemical signals that direct the migration of cells – particularly, the expression of chemokines CXCL1 and CXCL5.
To determine the clinical relevance of this gene expression profile, Moses and Bierie collaborated with Christine Chung, M.D., and biostatistician Yu Shyr, Ph.D., to probe human breast cancer gene expression profiles available in public databases.
They found that the gene signature representing a complete elimination of TGF-β signaling correlated with significantly reduced relapse-free survival in all patients. This association was even stronger in patients with estrogen receptor (ER) positive tumors, a subtype of breast cancer that responds well to anti-estrogen therapies like tamoxifen.
The results suggest that testing for this gene signature could aid in the prognosis and treatment of breast cancer, especially in ER positive tumors.
The signature also points to chemokines as important mediators of TGF-β's effects on tumor growth.