Targeting the epigenetics of the DNA damage response in breast cancer

Area of Science:

• Oncology
• Epigenetics
• Cancer Biology

Background:

• Epigenetic alterations are crucial in cancer development and progression.
• Targeting specific epigenetic machinery can be inefficient due to complex regulatory networks.
• Inhibiting the methionine cycle offers a global epigenetic strategy by affecting DNA and protein methylation.

Purpose of the Study:

• To develop an adjuvant therapy targeting the epigenetics of DNA damage response in breast cancer.
• To evaluate the efficacy of a combined therapy in inducing apoptosis and reducing metastasis.
• To investigate the impact of the therapy on DNA repair mechanisms and cancer stem cells.

Main Methods:

• A combined therapy using dipyridamole and a synthetic antifolate (3-O-(3,4,5-trimethoxybenzoyl)-(-)-catechin) was administered.
• The therapy's effect on folic and methionine cycles was assessed in breast cancer cells.
• Sensitivity to radiotherapy, DNA damage response (53BP1, BRCA1 recruitment), cancer stem cell self-renewal, and mesenchymal phenotype were evaluated.

Main Results:

• The combined therapy efficiently blocked both folic and methionine cycles in breast cancer cells.
• The treatment sensitized breast cancer cells to radiotherapy and impeded DNA damage response.
• The hypomethylating therapy reduced cancer stem cell self-renewal and induced reversion of mesenchymal phenotypes, reducing distant metastases in vivo.

Conclusions:

• This novel adjuvant therapy effectively targets breast cancer epigenetics, enhancing radiotherapy efficacy.
• The combined approach inhibits key pathways involved in DNA repair and cancer stemness.
• The findings suggest a promising strategy for reducing breast cancer progression and metastasis.