Polyamine Anabolism Promotes Chemotherapy-Induced Breast Cancer Stem Cell Enrichment.

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cytotoxic chemotherapy resistance and relapse are significant challenges in breast cancer treatment.
• Chemoresistant breast cancer stem cells (BCSCs) are implicated in cancer recurrence and metastasis.
• Targeting BCSCs is crucial for improving patient outcomes.

Purpose of the Study:

• To develop an mRNA-based signature for evaluating cancer stemness in breast cancer.
• To elucidate the role of polyamine anabolism in chemotherapy-induced BCSC enrichment.
• To identify and validate therapeutic strategies targeting BCSCs.

Main Methods:

• Machine learning applied to mRNA expression data from patient samples to create a BCSC signature.
• Investigated the mechanism of polyamine anabolism regulation by HIF-1 in response to chemotherapy.
• Screened a natural compound library to identify HIF-1 inhibitors, including britannin.
• Validated findings in vitro, in xenograft mice, and in autochthonous mouse models.

Main Results:

• An mRNA-based BCSC signature was developed to assess cancer stemness.
• Polyamine anabolism, regulated by HIF-1 activation of ODC1 and SRM, is critical for chemotherapy-induced BCSC enrichment.
• Genetic inhibition of HIF-1-controlled polyamine anabolism reduced BCSC enrichment.
• Britannin, a novel HIF-1 inhibitor, effectively suppressed BCSC enrichment and related molecular pathways in preclinical models.

Conclusions:

• Polyamine anabolism plays a key role in regulating breast cancer stem cells.
• Targeting HIF-1-mediated polyamine anabolism presents a promising therapeutic strategy for overcoming chemotherapy resistance in breast cancer.
• Britannin demonstrates potential as a co-adjuvant therapy to enhance breast cancer treatment efficacy.