Weight loss reduces basal-like breast cancer through kinome reprogramming

Area of Science:

• Oncology
• Metabolic Syndrome
• Cancer Biology

Background:

• Obesity is a known risk factor for aggressive basal-like breast cancer (BBC).
• Currently, no targeted therapies exist for BBC, highlighting the urgent need for mechanistic understanding.
• Reducing adult adiposity has been shown to decrease BBC incidence in humans.

Purpose of the Study:

• To investigate if dietary intervention reducing adiposity before tumor onset could reverse high-fat diet (HFD)-induced BBC.
• To explore the mechanisms underlying obesity and weight loss in BBC risk.

Main Methods:

• Adult mice were fed either a low-fat diet (LFD) or HFD, with an obese group switched from HFD to LFD to induce weight loss.
• Mammary glands were analyzed before tumor onset, and tumor latency, burden, and progression were evaluated.
• Physiological, histological, and proteomic analyses, including kinome analysis, were performed.

Main Results:

• Weight loss significantly delayed tumor latency, matching that of LFD-fed mice.
• Plasma leptin levels, elevated with adiposity, decreased with weight loss and correlated negatively with tumor latency.
• HFD increased pre-neoplastic lesions (atypical ductal hyperplasia, DCIS), which was prevented by weight loss.
• Kinome analysis revealed weight loss reversed HFD-induced activation of specific kinases (PKC-α, PKD1, PKA, MEK3) and increased AMPKα activity.

Conclusions:

• Pre-tumorigenesis weight loss protected against HFD effects on tumor latency and pre-neoplastic lesions.
• Kinomics identified novel kinase targets (e.g., upstream of MAPK/P38α) in obesity-associated BBC, reversed by weight loss.
• Weight loss reprogrammed the HFD-induced pro-tumorigenic microenvironment, restoring a lean phenotype and impacting mammary changes.