title: Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity.
abstract: Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL-a re-engineered protein form of the antioxidant enzyme catalase-inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c.
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Bao
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mitrea
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Priyanga
authors.initials: P
authors.lastname: Wijesinghe
authors.affiliation: The Microsoft Research - University of Trento Centre for Computational and Systems Biology, Rovereto, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Marchetti
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Girsch
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit MI 48201, USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Farr
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Boerner
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA.|Translational Research Institute, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Mohammad
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Dyson
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit MI 48201, USA.
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Terlecky
authors.affiliation: Barbara Ann Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Aliccia
authors.initials: A
authors.lastname: Bollig-Fischer
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005260:Female; D006801:Humans; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; D000069347:Erlotinib Hydrochloride