Combinatorial expression of microtubule-associated EB1 and ATIP3 biomarkers improves breast cancer prognosis

Nehlig

Kacem

et al. 2020

Sci Rep

Self Cite

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...

Section: Discussionsupporting

confidence: 73%

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

Nehlig

Kacem

et al. 2020

Sci Rep

Self Cite

“…To assess the clinical relevance of our findings, we analyzed a series of 88 breast cancer patients in whom ploidy had been evaluated. Tumors were grouped according to low and high MTUS1 levels using heat map classification as reported (24,28) and compared with ploidy status (SI Appendix, Table S5). As shown in Fig.…”

Section: Ptx-induced Mitotic Defects Are Increased In Atip3-deficientmentioning

confidence: 99%

Improving breast cancer sensitivity to paclitaxel by increasing aneuploidy

Proc. Natl. Acad. Sci. U.S.A.

Nehlig

Moindjie

et al. 2019

Self Cite

Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the MTUS1 gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy, which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive biomarker for a population of chemoresistant breast cancer patients.

“…In breast cancer, EB1 levels were found elevated at the mRNA and protein levels compared to normal tissue [54,55]. Furthermore, EB1 (but not EB2 or EB3) was identified as a prognostic biomarker whose high expression in breast tumors associates with tumor malignancy, high histological grade and reduced overall survival of the patients [55]. The observation that ATIP3 negatively regulates EB1 functions launched further studies to investigate the clinical relevance of ATIP3-EB1 interaction for breast cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Microtubule-associated tumor suppressors as prognostic biomarkers in breast cancer

Breast Cancer Res Treat

Molina

Nahmias

2019

Self Cite

Breast cancer is the most common malignancy in women worldwide. Although important therapeutic progress was achieved over the past decade, this disease remains a public health problem. In the light of precision medicine, the identification of new prognostic biomarkers in breast cancer is urgently needed to stratify populations of patients with poor clinical outcome who may benefit from new personalized therapies. The microtubule cytoskeleton plays a pivotal role in essential cellular functions and is an interesting target for cancer therapy. Microtubule assembly and dynamics are regulated by a wide range of microtubule-associated proteins (MAPs), some of which have oncogenic or tumor suppressors effects in breast cancer. This review covers current knowledge on microtubule-associated tumor suppressors (MATS) in breast cancer and their potential value as prognostic biomarkers. We present recent studies showing that combinatorial expression of ATIP3 and EB1, two microtubule-associated biomarkers with tumor suppressor and oncogenic effects, respectively, improves breast cancer prognosis compared to each biomarker alone. These findings are discussed regarding the increasing complexity of protein networks composed of MAPs that coordinate microtubule dynamics and functions. Further studies are warranted to evaluate the prognostic value of combined expression of different MATS and their interacting partners in breast cancer.