Mechanical control of breast cancer malignancy by promotion of mevalonate pathway enzyme synthesis

Area of Science:

• Biochemistry
• Cell Biology
• Cancer Research

Background:

• Breast cancer progression involves extracellular matrix (ECM) stiffening.
• Mechanotransduction from stiff ECM drives cancer cell proliferation and invasion.
• Metabolic reprogramming is crucial for cancer cell adaptation and growth.

Purpose of the Study:

• To investigate the role of ECM stiffness in regulating metabolic pathways in breast cancer.
• To identify key enzymes and signaling pathways involved in mechanotransduction-driven breast cancer progression.
• To explore HMGCS1 as a potential therapeutic target in breast cancer.

Main Methods:

• Utilized a matrix stiffening model mimicking breast cancer progression.
• Performed quantitative mass spectrometry to identify ECM-stiffness upregulated enzymes.
• Employed RNA interference (RNAi) to inhibit HMGCS1 expression.
• Investigated mechanotransduction signaling pathways involving integrin and Rac1.

Main Results:

• ECM stiffening upregulated mevalonate pathway enzymes, including HMGCS1, in breast cancer.
• HMGCS1 upregulation occurred at the post-transcriptional level, independent of mRNA changes.
• HMGCS1 inhibition via RNAi blocked stiffness-driven proliferation and invasion.
• Mechanotransduction signaling (integrin/Rac1) promoted HMGCS1 expression and malignant phenotype.

Conclusions:

• ECM stiffness drives breast cancer malignancy by reprogramming mevalonate pathway metabolism via HMGCS1.
• HMGCS1 is a critical mediator of mechanotransduction-induced breast cancer progression.
• Targeting HMGCS1 or its regulatory pathways may offer novel therapeutic strategies for breast cancer.