A balanced level of profilin-1 promotes stemness and tumor-initiating potential of breast cancer cells

ABSTRACT

Profilin-1 (Pfn1) is an important actin-regulatory protein that is downregulated in human breast cancer and when forcibly elevated, it suppresses the tumor-initiating ability of triple-negative breast cancer cells. In this study, we demonstrate that Pfn1 overexpression reduces the stem-like phenotype (a key biologic feature associated with higher tumor-initiating potential) of MDA-MB-231 (MDA-231) triple-negative breast cancer cells. Interestingly, the stem-like trait of MDA-231 cells is also attenuated upon depletion of Pfn1. A comparison of cancer stem cell gene (CSC) gene expression signatures between depleted and elevated conditions of Pfn1 further suggest that Pfn1 may be somehow involved in regulating the expression of a few CSC-related genes including MUC1, STAT3, FZD7, and ITGB1. Consistent with the reduced stem-like phenotype associated with loss-of-function of Pfn1, xenograft studies showed lower tumor-initiating frequency of Pfn1-depleted MDA-231 cells compared to their control counterparts. In MMTV:PyMT mouse model, homozygous but not heterozygous deletion of Pfn1 gene leads to severe genetic mosaicism and positive selection of Pfn1-proficient tumor cells further supporting the contention that a complete lack of Pfn1 is likely not conducive for efficient tumor initiation capability of breast cancer cells. In summary, these findings suggest that the maintenance of optimal stemness and tumor-initiating ability of breast cancer cells requires a balanced expression of Pfn1.

KEYWORDS:

• Breast cancer
• Profilin1
• stemness
• tumorigenicity

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Dr. Reinhard Fassler (Max Planck Institute) for the generous gift of Pfn1^flox/flox mouse. We also thank Drs. Anda Vlad and Lixin Zhang (University of Pittsburgh) for providing us the MUC1 antibody and helpful suggestions on MUC1 immunoblot.

Author contributions

CJ, ZJ, MJ, SC and SHK performed experiments, analyzed the data, and wrote the manuscript. RB generated the original Pfn1 floxed mouse and provided intellectual input to the manuscript. JC provided MMTV:PyMT mouse and intellectual input in the study design, SS provided intellectual input in the study design. PR conceived the study, designed experiments, and wrote the manuscript.

Additional information

Funding

This work was supported by a grant from the National Institute of Health (R01 2R01CA108707) to P.R.