Resistance to Taxanes in Triple-Negative Breast Cancer Associates with the Dynamics of a CD49f+ Tumor-Initiating Population

Abstract

SummaryTaxanes are a mainstay of treatment for breast cancer, but resistance often develops followed by metastatic disease and mortality. Aiming to reveal the mechanisms underlying taxane resistance, we used breast cancer patient-derived orthoxenografts (PDX). Mimicking clinical behavior, triple-negative breast tumors (TNBCs) from PDX models were more sensitive to docetaxel than luminal tumors, but they progressively acquired resistance upon continuous drug administration. Mechanistically, we found that a CD49f+ chemoresistant population with tumor-initiating ability is present in sensitive tumors and expands during the acquisition of drug resistance. In the absence of the drug, the resistant CD49f+ population shrinks and taxane sensitivity is restored. We describe a transcriptional signature of resistance, predictive of recurrent disease after chemotherapy in TNBC. Together, these findings identify a CD49f+ population enriched in tumor-initiating ability and chemoresistance properties and evidence a drug holiday effect on the acquired resistance to docetaxel in triple-negative breast cancer.

Sorafenib Inhibits Proliferation, Migration and Invasion of Breast Cancer Cells

“…3a, b). The cancer stem cells in breast cancer is defined by CD44 + / CD24 -/lo and CD49F expressing cells [23,24]. On treatment with sorafenib, we found a significant increase in CD24 expression in MDA-MB-231 cells indicating a reduction in the breast cancer stem cell population (Fig.…”

“…Ha et al [28] and Yoshida et al [29] reported similar inhibition of migration and invasion in hepatocellular carcinoma cells after sorafenib treatment. In association with reduced migration and in- Breast cancer stem cells, responsible for cancer initiation, progression, chemoresistance and recurrence were identified as CD44 + /CD24 -/lo along with other markers such ALDH and CD49F [23,24,30]. CD44 + /CD24 -/lo phenotype is enriched in basal like breast cancer and the majority of MDA-MB-231 cells have CD44 + /CD24 -/lo phenotype.…”

Chromosome 12p Amplification in Triple-Negative/BRCA1-Mutated Breast Cancer Associates with Emergence of Docetaxel Resistance and Carboplatin Sensitivity

“…We have recently shown that PDX models are suitable tools for the study of chemoresistance. We found that unlike luminal tumors, basal-like PDX models were initially sensitive to docetaxel (IDB-01S and IDB-02S) but they progressively develop resistance after continuous in vivo docetaxel treatment (IDB-01R and IDB-02R), mimicking the clinical scenario (17). A gene expression signature predicting residual disease after anthracycline/taxane-based therapy in patients with basal-like disease was identified using our paired docetaxel sensitive and resistant basallike PDX models, highlighting the clinical relevance of these models (17).…”

“…All research involving animals was performed in compliance with protocols approved by the Institutional Committees on Animal Care and adhering to European Union and international regulations. PDX models were generated as described (17). Findings from the IDB models were evaluated in an interim analysis of 2 ongoing PDX-based preclinical chemotherapy trials being conducted at Baylor College of Medicine to be described in full elsewhere upon completion.…”

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

“…CD49f is a marker associated with chemoresistant and tumor-initiating cell populations in TNBC [109]. We identified that NEAT1 expression is correlated with CD49f ( Table 2).…”