In the United States 1 in 8 women will be diagnosed with breast cancer within their lifetime, accounting for nearly 30% of cancer diagnoses annually. Although improvements have been made in early diagnoses and treatment, the heterogeneity of breast cancer often makes treatment of the disease a challenge. Triple negative breast cancer (TNBC) ranks as the 5th leading cause of cancer related death in women, while also being more prevalent in younger African American and Hispanic premenopausal women. The invasive nature of TNBC increases the risk of metastasis and recurrence, and patients will often acquire resistance to existing treatment options, emphasizing the need for new breast cancer therapies. A novel therapeutic approach is the inhibition of the highly abundant long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript (MALAT1) using an antisense oligonucleotide (ASO). MALAT1 has been shown to be upregulated in several breast cancer subtypes, increasing the migratory and invasive properties of tumor cells. Using a MALAT1 ASO in our preclinical syngeneic p53 null TNBC tumor mouse models, we were able to significantly knockdown MALAT1 RNA expression and observed a delay in primary tumor growth as well as an improvement in tumor response when used in combination with the chemotherapy drugs carboplatin or docetaxel. Additionally, immunophenotyping of tumor infiltrating lymphocytes show that MALAT1 inhibition alters the tumor microenvironment with a significant decrease in immunosuppressive CD206+ Arginase+ macrophages and myeloid derived suppressor cells (MDSC) as well as an increase in cytotoxic CD8+ T cells. The immuno-stimulatory effects of MALAT1 inhibition highlight the benefit of a MALAT1 ASO therapeutic and its potential to be used in combination with current chemotherapies and/or developing immunotherapies.
Citation Format: Oluwatoyosi Adewunmi, Jeffrey Rosen. LncRNA MALAT1 as a potential therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1541.