# The DAG/PKC/CREB1/TGF-β1 axis drives shear-wave elastography stiffness and malignant progression in triple-negative breast cancer via lipid metabolic reprogramming

## TL;DR

This study shows how lipid metabolism affects tumor stiffness and cancer progression in triple-negative breast cancer, offering a new way to predict prognosis and guide treatment.

## Contribution

The study identifies the DAG/PKC/CREB1/TGF-β1 axis as a key driver of tumor stiffness and malignancy in TNBC through lipid metabolic reprogramming.

## Key findings

- Elevated BMI and higher SWE stiffness are linked to poorer prognosis in TNBC patients.
- DAG promotes tumor stiffness and malignant progression via PKC/CREB1/TGF-β1 signaling.
- SWE stiffness reflects activation of a pro-metastatic pathway in TNBC.

## Abstract

In clinical practice, triple-negative breast cancer (TNBC) patients with varying levels of lipid metabolism exhibit differences in tumor shear-wave elastography (SWE) stiffness and prognosis, but this association with unclear mechanism. In this study, a clinical cohort from FUSCC (n = 147) demonstrated that both elevated BMI and higher SWE stiffness were significantly associated with poorer long-term prognosis in TNBC patients, and these associations were further validated in multi-TNBC animal models. Our findings emphasize the role of SWE stiffness in capturing BMI-related alterations in the tumor mechanical microenvironment. Based on integrated lipidomic and transcriptomic analyses, we demonstrated that diacylglycerol (DAG) serves as a critical lipid molecule promoting elevated SWE stiffness and malignant progression. Mechanistically, DAG upregulates TGF-β1 expression through PKC-mediated enhancement of CREB1 phosphorylation in multiple TNBC cell lines, directly promoting TNBC progression and activating cancer-associated fibroblasts. This creates a self-sustaining feedback loop that accelerates malignancy. Finally, we confirmed that the DAG/PKC/CREB1/TGF-β1 signaling axis profoundly regulates SWE imaging stiffness in TNBC models, with further validation in clinical samples. Our study establishes SWE stiffness as a non-invasive imaging biomarker for the activation of this specific pro-metastatic pathway, providing a mechanistic basis for interpreting SWE features through a biological lens and paving the way for its application in prognosis prediction and tailored therapeutic strategies for high-risk TNBC patients.