Abstract
Fibrous sheath-interacting protein 1 (FSIP1) functions centrally in breast carcinogenesis and progression, although its exact role remains to be clarified. Therefore, we sought to establish a correlation between the clinico-pathological features of breast cancer and FSIP1 expression in breast cancer tissues, as well as to validate its role in tumor progression and chemo-resistance. We analyzed FSIP1 expression in the breast cancer and para-tumor tissues by immunohistochemistry. We performed MTT, Caspase-Glo 3/7 Assay, Annexin V staining, wound healing and trans-well assays to evaluate cellular apoptosis, proliferation, migration and invasion in FSIP1 knockout and wild-type breast cancer cell lines. Additionally, we examined the effects of FSIP1 on docetaxel sensitivity in a nude mice model transplanted with control or FSIP1 knockout breast cancer cells, and also evaluate its role in tumor metastasis. FSIP1 and MRP1 interaction was determined by co-immunoprecipitation and mass spectrometry. We found that breast cancer cells and tissues consistently demonstrated elevated FSIP1 expressions, which correlated with poor overall survival. Notably, patients with high FSIP1 expression in their tumors undergoing docetaxel neoadjuvant chemotherapy had shorter disease-free survival. FSIP1 knockout in breast cancer cells significantly increased their sensitivity to docetaxel both in vitro and in vivo. Mechanistically, FSIP1 bound to the multidrug resistance protein 1 (MRP1) and stabilized it, and knocking out FSIP1 decreased MRP1 expression and increased cellular docetaxel accumulation. In sum, FSIP1 promotes breast carcinogenesis and mediates docetaxel resistance, and may serve as a novel target in the development of breast cancer therapies.
Highlights
Breast cancer is amongst the most frequently encountered cancers globally, laying claim to being a cancer with the second highest mortality rates in women
Fibrous sheath-interacting protein 1 (FSIP1) is over-expressed in breast cancer cell lines and tumor tissues
FSIP1 protein expression markedly increased in every breast cancer cell line when contrasted to the Human mammary epithelial cells (HMEC) (Fig. 1a)
Summary
Breast cancer is amongst the most frequently encountered cancers globally, laying claim to being a cancer with the second highest mortality rates in women. Over 1 million diagnoses of breast cancer are made in women with 400,000 deaths due to the disease occurring annually[1]. Despite considerable progress in the treatment and diagnosis of breast cancer over the past decade, the Resistance to anticancer agents is a large barrier in the successful management of multiple cancer types. Cancer cells contain ATP-binding cassette (ABC) transporter proteins, such as p-glycoprotein (P-gp), MRP1 and MRP2, that can prevent the intracellular accumulation of cytotoxic drugs via ATP-dependent efflux pumps[2]. The high expression levels of these proteins on cancer cells forms the key contributing factor in the development of chemoresistance.
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