More than 40% of patients with luminal breast cancer treated with endocrine therapy agent tamoxifen demonstrate resistance. Emerging evidence suggests tumor initiating cells (TICs) and aberrant activation of Src and Akt signaling drive tamoxifen resistance and relapse. We previously demonstrated that aryl hydrocarbon receptor ligand aminoflavone (AF) inhibits the expression of TIC gene α6-integrin and disrupts mammospheres derived from tamoxifen-sensitive breast cancer cells. In the current study, we hypothesize that tamoxifen-resistant (TamR) cells exhibit higher levels of α6-integrin than tamoxifen-sensitive cells and that AF inhibits the growth of TamR cells by suppressing α6-integrin-Src-Akt signaling. In support of our hypothesis, TamR cells and associated mammospheres were found to exhibit elevated α6-integrin expression compared with their tamoxifen-sensitive counterparts. Furthermore, tumor sections from patients who relapsed on tamoxifen showed enhanced α6-integrin expression. Gene expression profiling from the TCGA database further revealed that basal-like breast cancer samples, known to be largely unresponsive to tamoxifen, demonstrated higher α6-integrin levels than luminal breast cancer samples. Importantly, AF reduced TamR cell viability and disrupted TamR mammospheres while concomitantly reducing α6-integrin messenger RNA and protein levels. In addition, AF and small interfering RNA against α6-integrin blocked tamoxifen-stimulated proliferation of TamR MCF-7 cells and further sensitized these cells to tamoxifen. Moreover, AF reduced Src and Akt signaling activation in TamR MCF-7 cells. Our findings suggest elevated α6-integrin expression is associated with tamoxifen resistance and AF suppresses α6-integrin-Src-Akt signaling activation to confer activity against TamR breast cancer.
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.
Poly(ADP‐ribose) polymerase 1 (PARP1) regulates a myriad of DNA repair mechanisms to preserve genomic integrity following DNA damage. PARP inhibitors (PARPi) confer synthetic lethality in malignancies with a deficiency in the homologous recombination (HR) pathway. Patients with triple‐negative breast cancer (TNBC) fail to respond to most targeted therapies because their tumors lack expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Certain patients with TNBC harbor mutations in HR mediators such as breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2), enabling them to respond to PARPi. PARPi exploits the synthetic lethality of BRCA‐mutant cells. However, de novo and acquired PARPi resistance frequently ensue. In this review, we discuss the roles of PARP in mediating DNA repair processes in breast epithelial cells, mechanisms of PARPi resistance in TNBC, and recent advances in the development of agents designed to overcome PARPi resistance in TNBC.
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), carries a poor prognosis. African American women develop TNBC at disproportionately higher rates than women of other ethnic groups. Dibenzyl trisulfide (DTS), found expressed in the Jamaican plant Petiveria alliacea, has been shown to inhibit the growth of several cancer types. However, little is known about whether this plant isolate displays anticancer activity in TNBC cells from African American patients or modulates cytochrome P450 1 (CYP1) enzyme activity. This work, as part of an ongoing ethnopharmacology-based bioactivity screening, was designed to fill this deficit. African American TNBC (AA-TNBC) cells HCC1806 and MDA-MB-468 were treated with varying concentrations of DTS for 48 h and cell viability was assessed using the Alamar Blue assay. DTS potently inhibited the growth of HCC1806 and MDA-MB-468 cells, producing IC50 values of 10.6 ± 1.2μM and 10.3 ± 2.0μM, respectively. Additionally, we discovered that DTS induced apoptosis in these cells. Furthermore, we investigated the ability DTS to impact the activities of the CYP1 family of enzymes, which are known to convert procarcinogens to carcinogens. The IC50 values obtained for CYPs 1A1, 1A2 and 1B1 were 1.68 ± 0.3μM, 1.9 ± 0.2μM and 1.29 ± 0.3μM, respectively. These data indicate DTS exhibits potent inhibition of the activities of these enzymes. In particular, DTS was able to bind to CYP1A2 in accordance with irreversible kinetics. In addition, DTS reduced CYP1 mRNA expression in both cell lines. Our findings provide a rationale for in vivo evaluations of DTS as a potential candidate for chemoprevention and for treating AA-TNBC patients. Citation Format: Jonathan V. Wooten, Shaniece Wauchope, Nicole Mavingire, Petreena Campbell, JéAnn Watson, Maxine Gossell-Williams, Rupika Delgoda, Eileen Brantley. Plant isolate dibenzyl trisulfide potently inhibits cytochrome P450 1 enzyme activity and the growth of breast cancer cells derived from African American patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C126.
While anti-estrogen tamoxifen (Tam) effectively treats many patients with estrogen receptor positive (ER+) tumors, up to 40% experience relapse following resistance. Breast cancer stem cells (CSCs) within tumors greatly contribute to tamoxifen resistance (TamR) and exhibit unique molecular signatures that drive metastasis and promote relapse. Tumor suppressor miRNAs aid in suppressing breast cancer progression. We have previously shown that aryl hydrocarbon receptor (AhR)-ligand Aminoflavone disrupts the formation of spheres and inhibits the expression of putative stemness marker α6-integrin and α6-integrin-src-Akt signaling. We hypothesize that two AhR ligands, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and 3,3'-Diindolylmethane (DIM), exhibit anticancer properties in MCF-7 breast cancer cells by targeting the CSC population in an AhR-dependent fashion. We found that DIM and 5F 203 disrupted mammospheres derived from MCF-7 cells but demonstrated a reduced capacity to do so in mammospheres derived from AHR100 cells (MCF-7 variants that are AhR-unresponsive). Wound healing and colony forming assays respectively revealed that 5F 203 and DIM also decreased cell migration and cell proliferation in MCF-7 cells and to a much lesser extent in AhR100 cells. 5F 203 and DIM induced miR125b-2 expression and suppressed the expression of stemness-regulating genes such as α6-integrin, a predicted miR125b-2 target. The reduction in stemness-gene expression in MCF-7 cells was attenuated following pretreatment with AhR antagonist CH223191. These data suggest that AhR ligands such as DIM and 5F 203 confer their anticancer actions including those against breast CSCs in an AhR-dependent manner. Our data is expected to provide a rationale for the development of anticancer AhR ligands designed to combat ER+ breast cancer and decrease the risk of relapse. Citation Format: Eileen Brantley, Nicole Mavingire, Jonathan Wooten, Petreena Campbell. Aryl hydrocarbon receptor ligands 5F 203 and 3,3'-Diindolylmethane disrupt mammospheres derived from MCF-7 cells and induce tumor suppressor miR125b-2 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1304.
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