ATIP3 deficiency facilitates intracellular accumulation of paclitaxel to reduce cancer cell migration and lymph node metastasis in breast cancer patients

Abstract

Taxane-based chemotherapy is frequently used in neoadjuvant treatment of breast cancer patients to reduce tumor growth and lymph node metastasis. However, few patients benefit from chemotherapy and predictive biomarkers of chemoresistance are needed. The microtubule-associated protein ATIP3 has recently been identified as a predictive biomarker whose low levels in breast tumors are associated with increased sensitivity to chemotherapy. In this study, we investigated whether ATIP3 deficiency may impact the effects of paclitaxel on cancer cell migration and lymph node metastasis. Expression levels of ATIP3 were analyzed in a cohort of 133 breast cancer patients and classified according to lymph node positivity following neoadjuvant chemotherapy. Results showed that low ATIP3 levels are associated with reduced axillary lymph node metastasis. At the functional level, ATIP3 depletion increases cell migration, front-rear polarity and microtubule dynamics at the plus ends, but paradoxically sensitizes cancer cells to the inhibitory effects of paclitaxel on these processes. ATIP3 silencing concomitantly increases the incorporation of fluorescent derivative of Taxol along the microtubule lattice. Together our results support a model in which alterations of microtubule plus ends dynamics in ATIP3-deficient cells may favor intracellular accumulation of paclitaxel, thereby accounting for increased breast tumor sensitivity to chemotherapy. Breast cancer is a leading cause of death by malignancy in women worldwide. Cancer cell invasion to axillary lymph nodes is a frequent complication of the disease and is associated with poor patient prognosis. Neoadjuvant chemotherapy including taxanes and anthracyclins, administered prior to surgery, is a frequent regimen for a number of breast tumors 1. However, the proportion of patients who will benefit from chemotherapy remains low, reaching 15-20% in the whole population. The identification of predictive biomarkers, allowing the selection of patients at high risk to resist to chemotherapy, is urgently needed to orient clinicians' decisions. Achievement of pathological complete response (pCR), a surrogate marker of treatment efficiency, is characterized by complete eradication of all invasive cancer cells from the breast and axillary lymph nodes 1,2 , suggesting that chemotherapy not only affects tumor growth but also impairs cancer cell invasion and lymph node metastasis 3. Chemotherapeutic drugs such as paclitaxel and docetaxel (taxanes) are microtubule-targeting agents that bind and stabilize microtubules. Initially referred to as "mitotic poisons", because of their ability to block the mitotic spindle and impair chromosome segregation, taxanes were later shown to suppress microtubule dynamic instability when used at clinically relevant concentrations of the nanomolar range 4. At very low concentrations, taxanes are no longer able to regulate cell growth but are still effective in reducing cell migration and motility 5-8. In the search for predictive biomarkers of breast cancer sens...

MTUS1 is a promising diagnostic and prognostic biomarker for colorectal cancer

“…Previous studies have shown that the expression of MTUS1 is correlated with different cell phenotypes, such as proliferation, differentiation, apoptosis, and ubiquitination, and is a prognostic indicator for multiple cancers. MTUS1 can also regulate cell division by disturbing the microtubule cytoskeleton and can also be used to predict the treatment response to paclitaxel-based chemotherapy in breast cancer [ 21 – 23 ]. In lung adenocarcinoma tissues, low MTUS1 expression is related to various clinical-pathological parameters, such as tumour size, Ki-67 proliferation index, lymphovascular invasion, and lymph node metastasis, which lead to the correspondingly poor prognosis of patients [ 14 ].…”

“…Low expression levels of MTUS1 were significantly correlated with worse OS and DSS, which indicated that these patients had a trend of high survival risk. Logistic regression showed that the expression of MTUS1 in CRC was associated with advanced pathological stages and N stages, suggesting that MTUS1 is important for tumour invasion and lymph node MTUS1 can also regulate cell division by disturbing the microtubule cytoskeleton and can also be used to predict the treatment response to paclitaxel-based chemotherapy in breast cancer [21][22][23]. In lung adenocarcinoma tissues, low MTUS1 expression is related to various clinical-pathological parameters, such as tumour size, Ki-67 proliferation index, lymphovascular invasion, and lymph node metastasis, which lead to the correspondingly poor prognosis of patients [14].…”

MTUS1 is Correlated with Immune Infiltration and Acts as a Promising Diagnostic and Prognostic Biomarker for Colorectal Cancer.

“…Previous studies have shown that the mRNA expression level MTUS1 correlated with cell phenotypes such as cell proliferation, differentiation, apoptosis and ubiquitination and can serve as a prognostic indicator for multiple cancers. MTUS1 can regulates the process of cell division through disturbing microtubule cytoskeleton and has also demonstrated utility to predict treatment response to paclitaxelbased chemotherapy in breast cancer (21)(22)(23). In lung adenocarcinoma tissues, low MTUS1 expression is related to various clinical pathological parameters such as tumor size, Ki-67 proliferation index, lymphovascular invasion and lymph node metastasis, which leads to a correspondingly poor prognosis of patients (14).…”

Microtubule-Associated Protein ATIP3, an Emerging Target for Personalized Medicine in Breast Cancer

“…Interestingly, ATIP3 expression was significantly down-regulated in taxane-sensitive tumors achieving pathological complete response to chemotherapy [ 58 ], including in the BL1 subtype of TNBC [ 77 ]. Lymph node metastases were also significantly less frequent among low-ATIP3 expressing tumors following treatment with paclitaxel, compared with high-ATIP3 tumors [ 78 ]. These results were rather unexpected as ATIP3 deficiency is associated with increased microtubule dynamics [ 21 ], which is opposite to the microtubule-stabilizing effect of taxanes.…”

“…At the molecular level, ATIP3 depletion leads to increased accumulation of paclitaxel along the microtubule lattice [ 78 ], which accounts for higher sensitivity to low doses of chemotherapy. These results are consistent with in vitro findings that microtubule instability at the plus ends may improve Taxol binding to microtubules [ 79 ].…”