title: Mithramycin A sensitizes therapy-resistant breast cancer stem cells toward genotoxic drug doxorubicin.
abstract: Chemotherapy resistance is a major clinical challenge for the management of locally advanced breast cancer. Accumulating evidence suggests a major role of cancer stem cells (CSCs) in chemoresistance evoking the requirement of drugs that selectively target CSCs in combination with chemotherapy. Here, we report that mithramycin A, a known specificity protein (Sp)1 inhibitor, sensitizes breast CSCs (bCSCs) by perturbing the expression of drug efflux transporters, ATP-binding cassette sub-family G, member 2 (ABCG2) and ATP-binding cassette sub-family C, member 1 (ABCC1), survival factors, B-cell lymphoma 2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and, stemness regulators, octamer-binding transcription factor 4 (Oct4) and Nanog, which are inherently upregulated in these cells compared with the rest of the tumor population. In-depth analysis revealed that aberrant overexpression of Sp1 in bCSCs transcriptionally upregulates (1) resistance-promoting genes to protect these cells from genotoxic therapy, and (2) stemness regulators to sustain self-renewal potential of these cells. However, mithramycin A causes transcriptional suppression of these chemoresistant and self-renewal genes by inhibiting Sp1 recruitment to their promoters. Under such antisurvival microenvironment, chemotherapeutic agent doxorubicin induces apoptosis in bCSCs via DNA damage-induced reactive oxygen species generation. Cumulatively, our findings raise the possibility that mithramycin A might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to eliminate CSCs. This will consequently lead to the improvement of therapeutic outcome for the treatment-resistant breast carcinomas.
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Saha
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors.forename: Shravanti
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Mazumdar
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors.forename: Argha
authors.initials: A
authors.lastname: Manna
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors.forename: Poulami
authors.initials: P
authors.lastname: Khan
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors.forename: Arghya
authors.initials: A
authors.lastname: Adhikary
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors.forename: Kirti
authors.initials: K
authors.lastname: Kajal
authors.affiliation: Department of Surgery, SSKM Hospital, Kolkata, West Bengal, India.
authors.forename: Debarshi
authors.initials: D
authors.lastname: Jana
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
authors.forename: Gaurisankar
authors.initials: G
authors.lastname: Sa
authors.affiliation: Department of Physiology, Bankura Sammilani Medical College, Bankura, West Bengal, India.
authors.forename: Sanhita
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Surgery, SSKM Hospital, Kolkata, West Bengal, India.
authors.forename: Diptendra K
authors.initials: DK
authors.lastname: Sarkar
authors.affiliation: Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India. Electronic address: tanya@jcbose.ac.in.
authors.forename: Tanya
authors.initials: T
authors.lastname: Das
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D057170:Translational Research, Biomedical; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D004317:Doxorubicin; C066851:mithramycin A; D008926:Plicamycin