Targeting Breast Cancer Stem Cells with CRISPRi-mediated NOTCH۱ Inhibition and Genetically-modified Adenovirus Delivery

Cancer continues to be a leading cause of mortality globally, with its hallmark being the uncontrollable proliferation of abnormal cells that invade and destroy healthy tissue. Among the various types of cancer, breast cancer is affecting millions of women each year, a harrowing disease that instills profound fear, as it can spread aggressively and often strikes without warning, leaving behind a trail of trauma and loss. Its widespread reach and high mortality rates make it one of the most feared cancers in the world. Traditional treatments, including surgery, radiation, chemotherapy, and hormonal therapies, offer some hope but often fall short, with patients facing difficult side effects and inconsistent outcomes. This highlights the urgent need for more effective solutions. Gene therapy has emerged as a beacon of hope in this landscape. Offering the potential to address the root genetic causes of breast cancer, it opens up new avenues for treatment. Among the most promising innovations is CRISPR technology, which allows for precise genetic editing to target and potentially eradicate cancerous cells. CRISPR can be delivered through viral vectors, with adenoviruses being commonly used for their efficiency in transporting therapeutic genes to target cells. This combination of gene therapy and advanced delivery systems offers a glimmer of hope in the battle against breast cancer's devastation. Herein, we designed an adenovirus-based delivery complex, with Heregulin and hyaluronic acid (HA) protein ligands conjugated with adenoviruses surface proteins. These proteins specifically bind to HER۲ and CD۴۴ receptors with high affinity, which are commonly overexpressed on breast cancer cells (BCC) and breast cancer stem cells (BCSCs). This viral vector deliver a plasmid containing components of the CRISPR-Cas۹ medicated gene inhibition called CRISPRi, which is designed to silence the q gene from transcription. NOTCH۱ is overexpressed in a significant proportion of breast cancer patients, including those with TNBC, hormone receptor-positive (HR+) breast cancer, and HER۲-positive breast cancer. This gene plays a key role in the development of breast cancer stem cells, which are thought to be responsible for tumor recurrence and metastasi

کلیدواژه ها:

Breast Cancer ، CRISPRi ، NOTCH۱ ، Adenovirus