Prospects for breast cancer immunotherapy using microRNAs and transposable elements as objects.

Area of Science:

• Oncology
• Immunotherapy
• Epigenetics

Background:

• Chemoresistant breast cancer (BC) poses a significant clinical challenge, with limited efficacy of current immunotherapies like checkpoint inhibitors (PD-1/PD-L1) due to lack of biomarkers and potential toxicities.
• Retroelements, including endogenous retroviruses (HERV-K) and LINE1 retrotransposons, play a dual role in BC, contributing to carcinogenesis while also offering potential as diagnostic biomarkers.
• Current treatment limitations necessitate novel therapeutic strategies for BC, particularly for chemoresistant forms.

Purpose of the Study:

• To explore novel immunotherapy approaches for chemoresistant breast cancer (BC) by leveraging epigenetic modifications and retroelement activation.
• To investigate the potential of using viral mimicry strategies, including retroelement manipulation, for enhancing antitumor immune responses in BC.
• To identify specific microRNAs associated with transposon activity for targeted BC therapy.

Main Methods:

• Epigenetic activation of retroelements using inhibitors of DNA methyltransferase, histone deacetylase, and histone methyltransferase to stimulate interferon response against tumor cells.
• Utilizing reverse transcriptase inhibitors to suppress specific oncogenic retrotransposons and complementary microRNAs to silence others involved in BC carcinogenesis.
• Identification of 35 specific transposon-derived microRNA changes in BC to guide targeted therapy development.

Main Results:

• Epigenetic modification strategies can activate retroelements, leading to an enhanced immune response against tumor cells.
• Retroelements are implicated in BC carcinogenesis and are being explored as diagnostic biomarkers.
• Specific microRNA alterations associated with transposon activity in BC have been identified as potential therapeutic targets.

Conclusions:

• Epigenetic activation of retroelements presents a promising immunotherapy strategy for chemoresistant breast cancer.
• Simultaneous suppression of oncogenic retrotransposons and silencing of specific transposons via microRNAs offers a rational approach for BC treatment.
• Identified transposon-derived microRNAs can serve as guides for developing targeted therapies for breast cancer.