The Breast Cancer Stem Cells Traits and Drug Resistance

Abstract

Drug resistance is a major challenge in breast cancer (BC) treatment at present. Accumulating studies indicate that breast cancer stem cells (BCSCs) are responsible for the BC drugs resistance, causing relapse and metastasis in BC patients. Thus, BCSCs elimination could reverse drug resistance and improve drug efficacy to benefit BC patients. Consequently, mastering the knowledge on the proliferation, resistance mechanisms, and separation of BCSCs in BC therapy is extremely helpful for BCSCs-targeted therapeutic strategies. Herein, we summarize the principal BCSCs surface markers and signaling pathways, and list the BCSCs-related drug resistance mechanisms in chemotherapy (CT), endocrine therapy (ET), and targeted therapy (TT), and display therapeutic strategies for targeting BCSCs to reverse drug resistance in BC. Even more importantly, more attention should be paid to studies on BCSC-targeted strategies to overcome the drug resistant dilemma of clinical therapies in the future.

Keywords: breast cancer stem cell signaling pathways; breast cancer stem cells; clinical therapy; drug resistance; surface markers.

FIGURE 1

Self-renew in BCSCs. (A) Anticancer drugs are often utilized for treat BC, efficiently targeting breast cancer cells (BCCs) (blue cells), but not BCSCs (orange cells). The residual stem-like cell populations can drive a more aggressive BC and trigger recurrence. (B) BCSCs can form a new tissue by the balance of renewal and divisions.

FIGURE 2

Effective drugs delivery system in BCSCs. Nanoparticles, which modified by surface markers (CD44, CXCR4) ligands and intracellular molecular (micro RNAs, ALDH1) ligands, loaded with anti-cancer drugs, efficiently targeting BCSCs. The delivery system shows effectively reversal of drug resistance through dual inhibition of BCSCs via repressing both ex- and intracellular tumorigenic markers.

FIGURE 3

Major mechanisms of drug resistance in BCSCs. Drug resistance is not only a result of the activation of the self-renewal (Notch and Hh signaling pathway) and anti-apoptotic (PI3K/AKT/mTOR signaling) in BCSCs, but also a consequence of the promotion of metastasis (EMT and Wnt/β-catenin signaling pathway), anti-oxidative activity (NRF2 signaling) and ATP-binding cassette (ABC) transporter (ABCG2) activity in BCSCs.

FIGURE 4

The novel strategies of drug resistance reversal in BCSCs. These strategies mainly include inhibited proliferation ability (Hh, NF-κB signaling pathway) and self-renewal ability (EMT and Wnt/β-catenin signaling pathway), promoted DNA damage (ROS scavenging system and Mitochondrial metabolism) and apoptosis (Notch and FOXO/FASL/FAS signaling pathway).