title: Intrinsic Resistance to 5-Fluorouracil in a Brain Metastatic Variant of Human Breast Cancer Cell Line, MDA-MB-231BR.
abstract: Although drug resistance is often observed in metastatic recurrence of breast cancer, little is known about the intrinsic drug resistance in such metastases. In the present study, we found, for the first time, that MDA-MB-231BR, a brain metastatic variant of a human breast cancer cell line, was refractory to treatment with 5-fluorouracil (5-FU) even without chronic drug exposure, compared to its parent cell line, MDA-MB-231, and a bone metastatic variant, MDA-MB-231SCP2. Both the mRNA and protein levels of COX-2 and BCL2A1 in MDA-MB-231BR were significantly higher than those in MDA-MB-231 or MDA-MB-231SCP2. Neither the COX-2 inhibitor celecoxib nor the NF-κB inhibitor BAY11-7082 could sensitize MDA-MB-231BR to 5-FU, indicating that COX-2 plays little, if any, role in the resistance of MDA-MB-231BR to 5-FU. Although BCL2-family inhibitor ABT-263 failed to sensitize MDA-MB-231BR to 5-FU at a dose at which ABT-263 is considered to bind to BCL2, BCL2-xL, and BCL2-w, but not to BCL2A1, ABT-263 did sensitize MDA-MB-231BR to 5-FU to a level comparable to that in MDA-MB-231 at a dose of 5 μM, at which ABT-263 may disrupt intracellular BCL2A1 protein interactions. More importantly, BCL2A1 siRNA sensitized MDA-MB-231BR to 5-FU, whereas the overexpression of BCL2A1 conferred 5-FU-resistance on MDA-MB-231. These results indicate that BCL2A1 is a key contributor to the intrinsic 5-FU-resistance in MDA-MB-231BR. It is interesting to note that the drug sensitivity of MDA-MB-231BR was distinct from that of MDA-MB-231SCP2 even though they have the same origin (MDA-MB-231). Further investigations pertinent to the present findings may provide valuable insight into the breast cancer brain metastasis.
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
authors.forename: Atsunobu
authors.initials: A
authors.lastname: Sagara
authors.affiliation: Life Science Tokyo Advanced Research Center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Life Science Tokyo Advanced Research Center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
authors.forename: Maky
authors.initials: M
authors.lastname: Otsuka
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Karasawa
authors.affiliation: Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa city, Ishikawa, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.affiliation: Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.|Life Science Tokyo Advanced Research Center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.affiliation: Life Science Tokyo Advanced Research Center (L-StaR), Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, Japan.
authors.forename: Yoshinori
authors.identifier: http://orcid.org/0000-0002-6218-8710
authors.initials: Y
authors.lastname: Kato
mesh_terms: D000814:Aniline Compounds / Q000633:toxicity; D001932:Brain Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000633:toxicity; D060066:Protein Interaction Maps / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013449:Sulfonamides / Q000633:toxicity; D013450:Sulfones / Q000633:toxicity
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000814:Aniline Compounds; C096816:BCL2-related protein A1; D052246:Cyclooxygenase 2 Inhibitors; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013449:Sulfonamides; D013450:Sulfones; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D005472:Fluorouracil; C528561:navitoclax