Drug uptake-based chemoresistance in breast cancer treatment

Breast cancer is the most prevalent type of tumor and the second leading cause of death due to cancer among women. Although screening methods, diagnosis and therapeutic options have improved in the last decade, chemoresistance remains an important challenge. There is evidence relating breast cancer resistance with signaling pathways involving hormone and growth receptors, survival, apoptosis and the activation of efflux pumps. However, the resistance mechanisms linked to drug uptake are poorly understood, despite it often being observed that the drug content is lower in resistant cancer cells and that the entry of the drug into these cells is a limiting process for the subsequent therapeutic effect.In this review, we provide an overview of drug uptake-based resistance mechanisms developed by cancer cells in the four main types of chemotherapy used in breast cancer: anthracyclines, taxanes, oxazaphosphorines and platinum-based drugs. The contribution of tumor microenvironment to reduced drug-uptake and multidrug resistance is also analyzed. As a developing field, nanomedicine-based approaches provide promising opportunities to improve drug specific targeting, cell interaction and uptake into cancer cells. The endocytic-mediated pathways attributed to the different types of nanoformulations as well as the contribution of nanotherapeutics to overcoming chemoresistance affecting drug uptake in breast cancer will be described. New approaches focusing on drug uptake mechanisms could improve breast cancer chemotherapy, obtaining better dose-response outcomes and reducing toxic side effects.