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Putative tumor suppressor cytoglobin promotes aryl hydrocarbon receptor ligand–mediated triple negative breast cancer cell death
Author(s) -
Rowland Leah K.,
Campbell Petreena S.,
Mavingire Nicole,
Wooten Jonathan V.,
McLean Lancelot,
Zylstra Dain,
Thorne Gabriell,
Daly Devin,
Boyle Kristopher,
Whang Sonya,
Unternaehrer Juli,
Brantley Eileen J.
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.27887
Subject(s) - triple negative breast cancer , cancer research , aryl hydrocarbon receptor , estrogen receptor , breast cancer , cancer cell , cathepsin d , gene silencing , chemistry , biology , cancer , medicine , transcription factor , biochemistry , gene , enzyme
Abstract Nearly 40 000 women die annually from breast cancer in the United States. Clinically available targeted breast cancer therapy is largely ineffective in triple negative breast cancer (TNBC), characterized by tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2). TNBC is associated with a poor prognosis. Previous reports show that aryl hydrocarbon receptor (AhR) partial agonist 2‐(4‐amino‐3‐methylphenyl)‐5‐fluorobenzothiazole (5F 203) selectively inhibits the growth of breast cancer cells, including those of the TNBC subtype. We previously demonstrated that 5F 203 induced the expression of putative tumor suppressor gene cytoglobin (CYGB) in breast cancer cells. In the current study, we determined that 5F 203 induces apoptosis and caspase‐3 activation in MDA‐MB‐468 TNBC cells and in T47D ER + PR + Her2 − breast cancer cells. We also show that caspases and CYGB promote 5F 203–mediated apoptosis in MDA‐MB‐468 cells. 5F 203 induced lysosomal membrane permeabilization (LMP) and cathepsin B release in MDA‐MB‐468 and T47D cells. In addition, silencing CYGB attenuated the ability of 5F 203 to induce caspase‐3/‐7 activation, proapoptotic gene expression, LMP, and cathepsin B release in MDA‐MB‐468 cells. Moreover, 5F 203 induced CYGB protein expression, proapoptotic protein expression, and caspase‐3 cleavage in MDA‐MB‐468 cells and in MDA‐MB‐468 xenograft tumors grown orthotopically in athymic mice. These data provide a basis for the development of AhR ligands with the potential to restore CYGB expression as a novel strategy to treat TNBC.