Abstract
Fibrous sheath interacting protein 1 (FSIP1) is a cancer antigen expressed in the majority of breast cancer tissues and is associated with poor prognosis. However, the role of FSIP1 in the progression and drug sensitivity of triple-negative breast cancer (TNBC) has not been explored. Here, we show that FSIP1 deficiency by shRNA-mediated knockdown or CRISPR-Cas9-mediated knockout significantly inhibits the proliferation and invasion of TNBC cells and impairs chemotherapy-induced growth inhibition in vivo. Computational modeling predicted that FSIP1 binds to ULK1, and this was established by coimmunoprecipitation. FSIP1 deficiency promoted autophagy, enhanced AMP-activated protein kinase (AMPK) signaling, and decreased mechanistic target of rapamycin (mTOR) and Wnt/β-catenin activity. In contrast, knockdown of AMPK or inhibition of autophagy restored the sensitivity to chemotherapy drugs in TNBC cells. Our findings uncover a role of FSIP1 as well as mechanisms underlying FSIP1 action in drug sensitivity and may, therefore, aid in design of TNBC therapies.
Highlights
Fibrous sheath interacting protein 1 (FSIP1) is a cancer antigen expressed in the majority of breast cancer tissues and is associated with poor prognosis
We report that FSIP1 positively regulates the proliferation and invasion of triple-negative breast cancer (TNBC) cells, and its silencing promotes drug resistance by inducing autophagy, by reducing mitochondrial biogenesis, and by enhancing AMP-activated protein kinase activation
FSIP1 is a cancer/testis antigen and its expression is associated with poor prognosis in breast cancer [19, 20]
Summary
Fibrous sheath interacting protein 1 (FSIP1) is a cancer antigen expressed in the majority of breast cancer tissues and is associated with poor prognosis. While patients with luminal or HER2+ breast cancers can be treated with hormone and targeted therapies, patients with basal-like cancer, such as triple-negative breast cancer (TNBC), usually depend on chemotherapy drugs such as docetaxel, doxorubicin, and others [3, 4]. FSIP1 is expressed in TNBC, the role of FSIP1 in the proliferation and migration of TNBC has not been explored It is still unclear which cellular protein(s) bind to FSIP1 and how the interaction affects autophagy and sensitivity to common chemotherapeutic drugs, such as docetaxel and doxorubicin, in TNBC. Our data indicate that FSIP1 silencing inhibits the proliferation and migration of TNBC cells and the growth of implanted tumors but enhances drug resistance to docetaxel, doxorubicin, and other chemotherapeutic drugs by promoting autophagy
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