Relationship between RUNX1 and AXIN1 in ER-negative versus ER-positive Breast Cancer

ABSTRACT

RUNX1 plays opposing roles in breast cancer: a tumor suppressor in estrogen receptor-positive (ER⁺) disease and an oncogenic role in ER-negative (ER⁻) tumors. Potentially mediating the former, we have recently reported that RUNX1 prevents estrogen-driven suppression of the mRNA encoding the tumor suppressor AXIN1. Accordingly, AXIN1 protein expression was diminished upon RUNX1 silencing in ER⁺ breast cancer cells and was positively correlated with AXIN1 protein expression across tumors with high levels of ER. Here we report the surprising observation that RUNX1 and AXIN1 proteins are strongly correlated in ER⁻ tumors as well. However, this correlation is not attributable to regulation of AXIN1 by RUNX1 or vice versa. The unexpected correlation between RUNX1, playing an oncogenic role in ER⁻ breast cancer, and AXIN1, a well-established tumor suppressor hub, may be related to a high ratio between the expression of variant 2 and variant 1 (v2/v1) of AXIN1 in ER⁻ compared with ER⁺ breast cancer. Although both isoforms are similarly regulated by RUNX1 in estrogen-stimulated ER⁺ breast cancer cells, the higher v2/v1 ratio in ER⁻ disease is expected to weaken the tumor suppressor activity of AXIN1 in these tumors.

KEYWORDS:

• AXIN1 alternative splicing
• oncogene
• tumor suppressor

Disclosure of potential conflict interest

No potential conflicts of interest were disclosed

Acknowledgments

We thank Dr. Paulette Mhawech-Fauceglia for help with the scoring of the TMA and Meng Li of the USC Bioinformatics Service Program at the Norris Medical Library for helpful discussions.

Funding

We acknowledge NIH grants RO1 DK07112 and RO1 DK07112S from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to BF, who holds the J. Harold and Edna L. LaBriola Chair in Genetic Orthopedic Research at USC. This work was also supported by an award from the SC CTSI Pilot Funding Program to NC.