| Summary: | <i>ABCB1</i>, also known as <i>MDR1</i>, is a gene that encodes P-glycoprotein (P-gp), a membrane-associated ATP-dependent transporter. P-gp is widely expressed in many healthy tissues—in the gastrointestinal tract, liver, kidney, and at the blood–brain barrier. P-gp works to pump xenobiotics such as toxins and drugs out of cells. P-gp is also commonly upregulated across multiple cancer types such as ovarian, breast, and lung. Overexpression of <i>ABCB1</i> has been linked to the development of chemotherapy resistance across these cancers. In vitro work across a wide range of drug-sensitive and -resistant cancer cell lines has shown that upon treatment with chemotherapeutic agents such as doxorubicin, cisplatin, and paclitaxel, <i>ABCB1</i> is upregulated. This upregulation is caused in part by a variety of genetic and epigenetic mechanisms. This includes single-nucleotide variants that lead to enhanced P-gp ATPase activity without increasing <i>ABCB1</i> RNA and protein levels. In this review, we summarize current knowledge of genetic and epigenetic mechanisms leading to <i>ABCB1</i> upregulation and P-gp-enhanced ATPase activity in the setting of chemotherapy resistance across a variety of cancers.
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