Serine/Threonine-Protein Kinase 11 (STK11) Knockdown in Breast Cancer Cells Promote Bone Metastasis Progression

초록

Bone metastasis is a frequent sequalae of breast cancer progression, contributing to the significant morbidity and mortality of the afflicted patients. STK11 (also known as Liver ki-nase B1 or LKB1) is a tumor suppressor gene, and loss-of-function mutation is oncogenic in lung and breast cancers. STK11 mutation is associated with poor prognosis and recurrence of breast cancer. Co-mutations in KRAS and STK11 cause inferior responses to anti-PD1 thera-pies. We thus have investigated the role of STK11 in breast cancer bone metastasis. CRISPR/Cas9-mediated STK11 knockout in 4T1 murine triple-negative breast cancer cells resulted in a reduction of cell migration in vitro and expression of epithelial-to-mesenchymal tran-sition (EMT) markers such as E-cadherin compared with the scrambled-sequence controls without significantly affecting cell proliferation rates, suggesting that STK11 is necessary for migration and invasion of breast cancer cells. An orthotopic bone metastasis mouse model via intra-tibial tumor cell inoculation showed significantly increased angiogenesis in STK11 knockout tumor tissues compared with the scrambled sequence control.Additionally, STK11 knockout tumors grown in the subcutaneous space had increased CD11b+Gr1+ myeloid-de-rived suppressor cells (MDSC) and correspondingly reduced CD3+ T cells. Collectively, our data support the causal role of STK11 in breast cancer bone metastasis progression, via cell migration, EMT and suppression of anti-tumoral immunity. Further investigation of molecu-lar mechanisms, particularly the role of STK11 in counterbalancing anti-tumoral immunity, will be beneficial to better management of breast cancer bone metastasis.