Abstract
FOXP3 is an important X-linked suppressor of breast cancer. It is reported that FOXP3 is usually mutant, absent, or cytoplasmic distribution in breast cancer cells, which increases the risk of breast cancer. However, in our study the full-length FOXP3 transcript can be detected in breast cancer cells and nuclear FOXP3 is expressed in some breast cancer samples. Therefore, an important question is how the tumor-suppressive function of wild-type FOXP3 is negated in these cancers. We found that Gal-1 is a novel interacting protein of FOXP3 in breast cancer. Furthermore, our results show that the FKH domain in FOXP3 is essential for its interaction with Gal-1. Through ChIP-seq assay, we found that the expression of Gal-1 could inhibit a variety of target genes which were directly regulated by FOXP3. More importantly, these FOXP3-bound genes are involved in the development and metastasis of cancer. Furthermore, functional studies revealed that blocking the FOXP3/Gal-1 interaction restores the tumor-suppressive properties of FOXP3 in breast cancer cells. Finally, we observed that the nuclear abundance of Gal-1 was significantly higher in breast cancer tissues than that in adjacent normal tissues. In addition, we identified that the acidic extracellular microenvironment in breast cancer tissues causes Gal-1 to accumulate in the nucleus. Altogether, nuclear Gal-1 interferes with the binding of FOXP3 to DNA by interacting with the FKH domain of FOXP3, and it indicates a possible mechanism for the loss of the tumor-suppressive properties of FOXP3 in wild-type FOXP3-positive breast cancer.
Highlights
Introduction The transcription factorFOXP3 is a member of the FOX protein family, which contains a characteristic DNAbinding forkhead (FKH) domain[1]
We examined FOXP3 expression, in human primary breast cancer tissues, from 165 breast cancer patients
This suggests that FOXP3 is usually absent in breast cancer, there are a substantial number of breast cancer samples that are positive for FOXP3
Summary
Introduction The transcription factorFOXP3 is a member of the FOX protein family, which contains a characteristic DNAbinding forkhead (FKH) domain[1]. FOXP3 functions as the master regulator of Tregs[2]. FOXP3 expression in different tumor cells has been found. The suppression of FOXP3 expression can induce dysregulation of many oncogenes, such as MYC, SKP2, and ERBB2, which are involved in the progression of breast cancer[6,7,8,9]. FOXP3 is reported to suppress breast tumor progression, by physically interacting with Runx[110]. FOXP3 can suppress tumor growth, by regulating the expression of miR-146a/b11. FOXP3 plays an important role in breast cancer metastasis, by regulating the Official journal of the Cell Death Differentiation Association
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