Myosin 1e promotes breast cancer malignancy by enhancing tumor cell proliferation and stimulating tumor cell de-differentiation.

Jessica L Ouderkirk-Pecone,Mira Krendel,Christopher E Turner,Gregory J Goreczny,Arthur H Tatum,Sharon E Chase

doi:10.18632/oncotarget.10139

Abstract

Despite advancing therapies, thousands of women die every year of breast cancer. Myosins, actin-dependent molecular motors, are likely to contribute to tumor formation and metastasis via their effects on cell adhesion and migration and may provide promising new targets for cancer therapies. Using the MMTV-PyMT murine model of breast cancer, we identified Myosin 1e (MYO1E) as a novel tumor promoter. Tumor latency in mice lacking MYO1E was significantly increased, and tumors formed in the absence of MYO1E displayed unusual papillary morphology, with well-differentiated layers of epithelial cells covering fibrovascular cores, rather than solid sheets of tumor cells typically observed in this cancer model. These tumors were reminiscent of papillary breast cancer in humans that is typically non-invasive and often cured by tumor excision. MYO1E-null tumors exhibited decreased expression of the markers of cell proliferation, which was recapitulated in primary tumor cells derived from MYO1E-null mice. In agreement with our findings, meta-analysis of patient survival data indicated that MYO1E expression level was associated with reduced recurrence-free survival in basal-like breast cancer. Overall, our data suggests that MYO1E contributes to breast tumor malignancy and regulates the differentiation and proliferation state of breast tumor cells.

Highlights

For women in the United States, breast cancer is the second most common cancer, resulting in 15% of deaths [1]
The current study is the first to characterize the role of a specific myosin in breast cancer progression using a mouse knockout model
Using the well-characterized MMTV-PyMT model of breast cancer, we identify Myosin 1e (MYO1E) as an important contributor to malignancy, regulating tumor progression and metastasis

Summary

Introduction

For women in the United States, breast cancer is the second most common cancer, resulting in 15% of deaths [1]. Perhaps one of the best-characterized mouse breast cancer models is the mouse mammary tumor virus-polyoma middle T antigen (MMTV-PyMT) model. The polyoma middle T antigen is a protein encoded by the polyomavirus genome that, when constitutively expressed in mammary epithelium, interacts with phosphoinositide-3-kinase (PI3K) and src kinase family members, promoting activation of the signaling pathways that are normally induced by growth factor receptors [5,6,7]. MMTV-PyMT mice exhibit spontaneous tumor formation within the ducts of the mammary glands [8, 9]. Tumors in the MMTV-PyMT mice arise from luminal epithelial cells, and the progression of tumors in this model best recapitulates the transition of human breast cancer from a non-invasive to invasive phenotype [3]. Initial tumor formation is confined within mammary ducts, and as tumors progress, the basement membrane is breached, facilitating cancer cell metastasis

Methods

Results

Conclusion