The interplay between replication stress and inflammatory signaling in breast cancer

Breast cancer is the most commonly diagnosed cancer among women worldwide. Triple-negative breast cancer (TNBC) typically displays more aggressive behavior and shows the worst prognosis. Genomic instability is one of the hallmarks of cancer and drives malignant tumor traits. A main driver of genomic instability in cancer is ‘replication stress’ (RS). RS is defined as slowing, stalling or aberrantly acceleration in replication fork progression. Higher levels of genomic instability have been linked to activation of the innate immunity via the cytoplasmic DNA sensing pathway including cGAS-STING signaling.
In this thesis, we studied the expression of cGAS-STING signaling in relation to RS markers, immune cell infiltration and response to immunotherapy in breast cancer patients. We also developed a functional ex vivo DNA fiber assay to measure RS levels for breast cancer tissue. Meanwhile, the activated interferon signaling play important roles in regulating DNA damage response reciprocally. We showed that higher levels of type I interferon signaling improved sensitivity of TNBC cells to genotoxic chemotherapies by elevating RS. Additionally, we also showed the roles of key RS-inducing oncogene, Cyclin E1, in regulating anti-tumor immune microenvironment. Altogether, our work provides new insights into the interaction between RS and cGAS-STING inflammatory signaling.