Role of ABCB1 in mediating chemoresistance of triple-negative breast cancers

Abstract

Triple-negative breast cancer (TNBC) is a group of breast cancers which neither express hormonal receptors nor human epidermal growth factor receptor. Hence, there is a lack of currently known targeted therapies and the only available line of systemic treatment option is chemotherapy or more recently immune therapy. However, in patients with relapsed disease after adjuvant or neoadjuvant therapy, resistance to chemotherapeutic agents has often developed, which results in poor treatment response. Multidrug resistance (MDR) has emerged as an important mechanism by which TNBCs mediate drug resistance and occurs primarily due to overexpression of ATP-binding cassette (ABC) transporter proteins such as P-glycoprotein (Pgp). Pgp overexpression had been linked to poor outcome, reduced survival rates and chemoresistance in patients. The aim of this mini-review is to provide a topical overview of the recent studies and to generate further interest in this critical research area, with the aim to develop an effective and safe approach for overcoming Pgp-mediated chemoresistance in TNBC.

Keywords: breast cancers; multidrug resistance; p-glycoprotein; triple negative breast cancer.

Figure 1. Pgp structure

Pgp structure composes of two transmembrane domains (TMDs) and two cytoplasmic domains (NBDs) which are the sites for ATP hydrolysis. Each TMD consists of six helices. Pgp molecule has NH₂– and COOH– termini within the cytoplasm.

Figure 2. Pgp confers MDR via a dual mechanism

(A) Pgp localized on the plasma membrane protects the cell by effluxing substrates out of the cells. During endocytosis, which is further facilitated by the tumor microenvironmental stressors, the plasma membrane invaginates, which results in topical inversion of Pgp orientation in the membrane of early endosome. The endosomes then mature into lysosomes with Pgp on their membrane still being functional with its active sites facing the cytosol. When a Pgp substrate, such as Paclitaxel enters the cells, it is not only pumped out via plasma membrane Pgp, but also pumped into lysosomes via lysosomal Pgp. Weakly basic Pgp substrates (ex: paclitaxel) tends to get entrapped within the lysosome through their ionization at the lysosomal pH. This mechanism leads to inactivity of Pgp substrates which target other organelles in the cell such as nucleus for paclitaxel. (B) In contrast, lysosomal targeting agents such as DpC hijacks this resistance pathway to induce lysosomal damage, which results in potent anti-cancer activity.