# The WISP1/Src/MIF Axis Promotes the Malignant Phenotype of Non-Invasive MCF7 Breast Cancer Cells

## TL;DR

This study shows that WISP1, through the Src/MIF axis, promotes invasive traits in breast cancer cells, suggesting a new target for ER-positive breast cancer therapy.

## Contribution

The study identifies a novel WISP1/Src/MIF signaling axis that drives invasive behavior in non-invasive breast cancer cells.

## Key findings

- WISP1 induces MIF expression and promotes epithelial-to-mesenchymal transition (EMT) in MCF7 breast cancer cells.
- The WISP1/Src/MIF axis affects extracellular matrix remodeling and hyaluronan metabolism in the tumor microenvironment.
- Src kinases and MIF are critical for the invasive phenotype induced by WISP1 in breast cancer cells.

## Abstract

What are the main findings?
WISP1 drives metastatic plasticity in ER+ breast cancer through Src-dependent induction of MIF.The WISP1/Src/MIF axis promotes EMT, extracellular matrix remodeling, and invasiveness of breast cancer cells.

WISP1 drives metastatic plasticity in ER+ breast cancer through Src-dependent induction of MIF.

The WISP1/Src/MIF axis promotes EMT, extracellular matrix remodeling, and invasiveness of breast cancer cells.

What are the implications of the main findings?
WISP1 regulates hyaluronan metabolism and proteolytic activity reshaping the tumor microenviroment.The WISP1/Src/MIF axis may serve as a therapeutic target in ER-positive breast cancer.

WISP1 regulates hyaluronan metabolism and proteolytic activity reshaping the tumor microenviroment.

The WISP1/Src/MIF axis may serve as a therapeutic target in ER-positive breast cancer.

Breast cancer is a heterogeneous disease that exists in multiple subtypes, some of which still lack targeted and effective therapy. A major challenge is to unravel their underlying molecular mechanisms and bring to light novel therapeutic targets. In this study, we investigated the role of WNT-inducible signaling pathway protein 1 (WISP1) matricellular protein in the acquirement of an invasive phenotype by breast cancer cells. To this aim, we treated non-invasive MCF7 cells with WISP1 and assessed the expression levels of macrophage migration inhibitory factor (MIF) and its cellular receptor CD74. Next, we examined the expression of epithelial-to-mesenchymal transition (EMT) markers as well as molecular effectors of the tumor microenvironment, such as CD44, the main hyaluronan receptor that also acts as a co-receptor for MIF, the hyaluronan oncogenic network, and specific matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). The results showed that WISP1 potently induces the expression of MIF cytokine and affects the expression of specific extracellular matrix molecules with established roles in the promotion of malignant properties. Notably, Src kinases and MIF are critically involved in these processes. Collectively, the present study demonstrates for first time a WISP1/Src/MIF axis as well as its ability to induce an invasive phenotype in MCF7 cells and highlights novel cellular and molecular processes involved in the epithelial-to-mesenchymal transition and the development of invasive breast cancer. This suggests that specific cues from the tumor microenvironment can activate a migratory/invasive phenotype in a subpopulation of cells residing within the heterogeneous breast tumor.