Background/Aim: Triple negative cancer (TNBC) is a subtype of breast cancer that is highly aggressive, with poor prognosis and responds differently to treatments. This study investigated the role of vorinostat and indole-3carbinol (I3C) on regulating critical receptors that are not normally expressed in TNBC. Materials and Methods: Using real-time PCR, immunostaining, and western blots, the reexpression of estrogen receptor α (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) receptors was examined in four different TNBC cell types. Results: ERα was re-expressed in three subtypes using vorinostat and I3C. Re-expression of the PR by vorinostat was also detected. Neither vorinostat nor I3C resulted in re-expression of the HER2 receptor. A significant decrease in growth and sensitivity to tamoxifen was also noted. Conclusion: The results of this study show that vorinostat and I3C modulate the re-expression of critical receptors in certain subtypes of TNBC through several pathways and these effects can be influenced by the molecular profiles of TNBCs.

Aberrantly expression of histone deacetylases (HDAC) play a critical role in tumorigenesis. The expression of individual HDACs has been shown to correlate to decreases in both, disease-free and overall survival, thus targeting HDACs is emerging as a new therapy for cancer. Histone acetylation is associated with elevated transcription, while deacetylation is associated with gene repression. Emerging evidence suggests their role in triple negative breast cancer (TNBC) progression. TNBC is an aggressive type of cancer that has poor prognosis and molecular studies have shown several subtypes within TNBC. These cancers lack targeted treatments and several options used such as, PARP inhibitors, angiogenesis inhibitors, androgen receptor inhibitors and others have shown limited efficacy, however histone deacetylase inhibitors are showing promising results in clinical trials. Vorinostat, a histone deacetylase inhibitor, also known as suberanilohydroxane acid (SAHA) was approved by the FDA for treatment of cutaneous T cell lymphoma. In this study, vorinostat was investigated in subtypes of TNBC cell lines, MB231(MSL) and two basal-like 2 TNBC cell lines, HCC70 and HCC1806. Cells were treated with vorinostat for 24 hrs. Vorinostat significantly up-regulated the tumor suppressor gene NR4A1 by 20 fold, NR4A3 by 10 fold and AR5A by 5 fold. RORα gene had the highest up-regulation, 60 fold, whereas PPARγ 4.5 fold. Estrogen related receptor A, ESRRA was also up-regulated in HCC70 cells. A decrease in expression was noted in DDX5, which is known to be elevated in basal-like tumors. A different profile was noted in the MB231 TNBC cells. Vorinostat also decreased growth and cell invasion, which shows its functional effects on these aggressive TNBC cell lines These changes suggest that vorinostat, which is currently in clinical trials for TNBC may be exerting its effect through modulation of orphan nuclear receptors and reactivation of tumor suppressor genes through epigenetic mechanisms. Further studies are needed to determine other signaling pathways modulated by this HDAC inhibitor. Citation Format: Fatemeh NouriEmamzadeh, Beverly Word, Ebony Cotton, Kai Littlejohn, Gustavo Miranda-Carboni, Beverly Lyn-Cook. Vorinostat exhibits anticancer effects through modulation of nuclear receptors and tumor suppressor genes in sub-types of triple negative breast cancer cells [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 5196.

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that often strikes young women, particularly minority women in their reproductive years. This cancer is very aggressive and has a poor prognosis mainly, due to the lack of effective chemotherapeutic agents. Recently, molecular profiling of a patients’ tumors yielded detection of specific driver genes in primary tumors that resulted in the use of a single or combination therapies targeting those driver genes. Triple negative breast cancers present an additional problem, in that they are found in different forms or subtypes histologically and molecularly. Basal 2 subtype is one of the most aggressive form of TNBC. Studies have shown that histologically designated tumors yield different treatment results. This study examined the molecular profiles of two Basal 2 triple negative breast cancers representing two different African American women and their response to vorinostat. Using a RT2 Profiler PCR gene expression array, vorinostat was found to up-regulate 54 genes and downregulated 3 genes in HCC70 TNBC. In HCC1806, 23 genes were upregulated and 38 downregulated. The most significant changes in gene expression were noted in CCND2 expression. Changes were also noted in SNA12, SERPINE, SLC39A6, AR, BRAC1 and TWIST. In HCC1806, significant changes in gene expression were noted in ABCB1, CCND2, CDKN1C and MMP9. Up-regulation of CCND2 was observed in both basal 2 cell lines. CCND2 encodes cyclin D2 in which low expression is associated with poor prognosis. Understanding individual differences in cancer driver genes will greatly improved personalized medicine in triple negative breast cancer. Citation Format: Beverly Word, Ebony Cotton, George Hammons, Beverly Lyn-Cook, Density Stovall. Molecular profiling of basal 2 subtypes of triple negative breast cancer cells and their response to a histone deacetylase inhibitor [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-218.

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Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that often strikes young women, particularly minority women in their reproductive years. This cancer has a poor prognosis, mainly due to the lack of effective chemotherapeutic agents. Triple negative breast cancers present an additional problem, in that a histologically subtype can have molecularly different forms. Studies have shown that histological designated tumors yield different treatment results. Recently, molecular profiling of a patient’s tumor yielded detection of specific driver genes that resulted in the use of single or combination therapies targeting these driver genes. Basal 2 subtype is one of the most aggressive form of TNBC. This study examined the molecular profiles of two Basal 2 triple negative breast cancers representing two different African American women in response to treatment with vorinostat. Using a RT2 Profiler PCR gene expression array, vorinostat up-regulated 54 genes and downregulated 3 genes in HCC70 TNBC. In HCC1806 TNBC, 23 genes were upregulated and 38 downregulated. The most significant change in gene expression noted in HCC70 was in CCND2, which is hypermethylated in TNBC. Changes were also noted in SNA12, SERPINE, and TWIST. In HCC1806, significant changes in gene expression were noted in ABCB1, CCND2, CDKN1C and MMP9. These results clearly demonstrated that there is a differential response to a potential anti-tumor drug by different molecular subtypes. Up-regulation of CCND2 was observed in both basal 2 cell lines. CCND2 encodes cyclin D2 in which low expression is associated with poor prognosis. Understanding individual differences in cancer driver genes will greatly improve personalized medicine in TNBC. Citation Format: Beverly Lyn-Cook, Destiny Stovall, Beverly Word, Ebony Cotton, George Hammons. Molecular profiling basal 2 subtypes of triple-negative breast cancer cells and their response to histone deacetylase inhibitor [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B125.