Integration of a pharmacist-led pharmacogenomic service in a geriatric clinic: Barriers and outcomes.

OBJECTIVES: The primary objective was to identify the proportion of patients who successfully completed PGx testing. Secondary objectives included determining the proportion of patients with actionable PGx results, determining the proportion of patients with a baseline medication intervention within 6 months of successfully completing PGx testing, and identifying barriers for not completing testing. DESIGN: This was a single center, non-interventional, retrospective cohort study, approved by the institutional review board. SETTING AND PARTICIPANTS: Patients included were 65 years of age or older and referred for PGx testing from geriatric outpatient clinics between May 1, 2019 and July 31, 2020. OUTCOME MEASURES: This study aimed to assess the implementation of pharmacist-led pharmacogenomics (PGx) in the care of community-dwelling older adults in an outpatient clinic. Little is known about the acceptance and impact of this type of service within this population. RESULTS: Of the 67 patients included, majority were female (78%), white (76%), and an average age of 78 years ± 5.98 SD. Majority were insured by Original Medicare or Medicaid (61%), had a history of cognitive impairment (84%), had a referring diagnosis of anxiety (40%) or depression (67%), and were prescribed a selective serotonin reuptake inhibitor (69%) at baseline. Majority successfully completed PGx testing (72%), with 72% having actionable PGx findings and 83% having a pharmacological intervention made thereafter. Nineteen patients did not complete testing (28%), with the primary barrier being not having an appointment scheduled (63%). CONCLUSION: This study demonstrated majority of older adults were accepting of PGx testing and majority of findings were relevant to clinical care of anxiety, depression, or cognitive impairment.

Pharmacogenomics meets precision cardio-oncology: is there synergistic potential?

An individual's inherited genetic makeup and acquired genomic variants may account for a significant portion of observable variability in therapy efficacy and toxicity. Pharmacogenomics (PGx) is the concept that treatments can be modified to account for these differences to increase chances of therapeutic efficacy while minimizing risk of adverse effects. This is particularly applicable to oncology in which treatment may be multimodal. Each tumor type has a unique genomic signature that lends to inclusion of targeted therapy but may be associated with cumulative toxicity, such as cardiotoxicity, and can impact quality of life. A greater understanding of therapeutic agents impacted by PGx and subsequent implementation has the potential to improve outcomes and reduce risk of drug-induced adverse effects.

Pharmacogenomics: An evolving clinical tool for precision medicine.

Pharmacogenomics, ie, the study of how an individual's genomic profile influences his or her response to drugs, has emerged as a clinical tool to optimize drug therapy. Certain variants in some genes increase the risk of severe, life-threatening adverse effects from certain drugs. Integrating pharmacogenomics into clinical practice to assist in drug selection and dosing has the potential to improve the outcomes of treatment, reduce the risk of drug-induced morbidity and death, and be cost-effective.

Involvement of a specificity proteins-binding element in regulation of basal and estrogen-induced transcription activity of the BRCA1 gene.

INTRODUCTION: Increased estrogen level has been regarded to be a risk factor for breast cancer. However, estrogen has also been shown to induce the expression of the tumor suppressor gene, BRCA1. Upregulation of BRCA1 is thought to be a feedback mechanism for controlling DNA repair in proliferating cells. Estrogens enhance transcription of target genes by stimulating the association of the estrogen receptor (ER) and related coactivators to estrogen response elements or to transcription complexes formed at activator protein (AP)-1 or specificity protein (Sp)-binding sites. Interestingly, the BRCA1 gene lacks a consensus estrogen response element. We previously reported that estrogen stimulated BRCA1 transcription through the recruitment of a p300/ER-alpha complex to an AP-1 site harbored in the proximal BRCA1 promoter. The purpose of the study was to analyze the contribution of cis-acting sites flanking the AP-1 element to basal and estrogen-dependent regulation of BRCA1 transcription. METHODS: Using transfection studies with wild-type and mutated BRCA1 promoter constructs, electromobility binding and shift assays, and DNA-protein interaction and chromatin immunoprecipitation assays, we investigated the role of Sp-binding sites and cAMP response element (CRE)-binding sites harbored in the proximal BRCA1 promoter. RESULTS: We report that in the BRCA1 promoter the AP-1 site is flanked upstream by an element (5'-GGGGCGGAA-3') that recruits Sp1, Sp3, and Sp4 factors, and downstream by a half CRE-binding motif (5'-CGTAA-3') that binds CRE-binding protein. In ER-alpha-positive MCF-7 cells and ER-alpha-negative Hela cells expressing exogenous ER-alpha, mutation of the Sp-binding site interfered with basal and estrogen-induced BRCA1 transcription. Conversely, mutation of the CRE-binding element reduced basal BRCA1 promoter activity but did not prevent estrogen activation. In combination with the AP-1/CRE sites, the Sp-binding domain enhanced the recruitment of nuclear proteins to the BRCA1 promoter. Finally, we report that the MEK1 (mitogen-activated protein kinase kinase-1) inhibitor PD98059 attenuated the recruitment of Sp1 and phosphorylated ER-alpha, respectively, to the Sp and AP-1 binding element. CONCLUSION: These cumulative findings suggest that the proximal BRCA1 promoter segment comprises cis-acting elements that are targeted by Sp-binding and CRE-binding proteins that contribute to regulation of BRCA1 transcription.

Cyclooxygenase-2 promoter activation by the aromatic hydrocarbon receptor in breast cancer mcf-7 cells: repressive effects of conjugated linoleic acid.

The role of the aromatic hydrocarbon receptor (AhR) in transcriptional regulation of the human cyclooxygenase-2 (COX-2) gene remains elusive. We report that the AhR-ligands benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced transcription activity of COX-2 in breast cancer MCF-7 cells. The TCDD-dependent activation of the COX-2 promoter was abrogated by mutation of 2 xenobiotic response elements (XREs) = CGTG). We found that TCDD stimulated the binding of the AhR to COX-2 and cytochrome P4501A1 (CYP1A1) oligonucleotides containing consensus XREs. Conversely, the cotreatment with TCDD plus a mixture of conjugated linoleic acid (CLA) or selected CLA isomers prevented (CLAmix = t10,c12-CLA > c9,t11-CLA) the induction of transcription from the COX-2 promoter. The TCDD-induced binding of the AhR to COX-2 and CYP1A1 oligonucleotides was repressed by cotreatment with CLA (t10,c12-CLA > c9,t11-CLA), and the AhR antagonists, 3-methoxy-4-naphthoflavone, and resveratrol. We conclude that the AhR may be a suitable target for prophylactic strategies that target COX-2 expression.

The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen.

In sporadic breast cancers, BRCA-1 expression is down-regulated in the absence of mutations in the BRCA-1 gene. This suggests that disruption of BRCA-1 expression may contribute to the onset of mammary tumors. Environmental contaminants found in industrial pollution, tobacco smoke, and cooked foods include benzo(a)pyrene [B(a)P] and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which have been shown to act as endocrine disruptors and tumor promoters. In previous studies, we documented that estrogen (E2) induced BRCA-1 transcription through the recruitment of an activator protein-1/estrogen receptor-alpha (ER alpha) complex to the proximal BRCA-1 promoter. Here, we report that activation of BRCA-1 transcription by E2 requires occupancy of the BRCA-1 promoter by the unliganded aromatic hydrocarbon receptor (AhR). The stimulatory effects of E2 on BRCA-1 transcription are counteracted by (a) cotreatment with the AhR antagonist 3'-methoxy-4'-nitroflavone; (b) transient expression in ER alpha-negative HeLa cells of ER alpha lacking the protein-binding domain for the AhR; and (c) mutation of two consensus xenobiotic-responsive elements (XRE, 5'-GCGTG-3') located upstream of the ER alpha-binding region. These results suggest that the physical interaction between the unliganded AhR and the liganded ER alpha plays a positive role in E2-dependent activation of BRCA-1 transcription. Conversely, we show that the AhR ligands B(a)P and TCDD abrogate E2-induced BRCA-1 promoter activity. The repressive effects of TCDD are paralleled by increased recruitment of the liganded AhR and HDAC1, reduced occupancy by p300, SRC-1, and diminished acetylation of H4 at the BRCA-1 promoter region flanking the XREs. We propose that the ligand status of the AhR modulates activation of the BRCA-1 promoter by estrogen.

An estrogen receptor-alpha/p300 complex activates the BRCA-1 promoter at an AP-1 site that binds Jun/Fos transcription factors: repressive effects of p53 on BRCA-1 transcription.

One of the puzzles in cancer predisposition is that women carrying BRCA-1 mutations preferentially develop tumors in epithelial tissues of the breast and ovary. Moreover, sporadic breast tumors contain lower levels of BRCA-1 in the absence of mutations in the BRCA-1 gene. The problem of tissue specificity requires analysis of factors that are unique to tissues of the breast. For example, the expression of estrogen receptor-alpha (ER alpha) is inversely correlated with breast cancer risk, and 90% of BRCA-1 tumors are negative for ER alpha. Here, we show that estrogen stimulates BRCA-1 promoter activity in transfected cells and the recruitment of ER alpha and its cofactor p300 to an AP-1 site that binds Jun/Fos transcription factors. The recruitment of ER alpha/p300 coincides with accumulation in the S-phase of the cell cycle and is antagonized by the antiestrogen tamoxifen. Conversely, we document that overexpression of wild-type p53 prevents the recruitment of ER alpha to the AP-1 site and represses BRCA-1 promoter activity. Taken together, our findings support a model in which an ER alpha/AP-1 complex modulates BRCA-1 transcription under conditions of estrogen stimulation. Conversely, the formation of this transcription complex is abrogated in cells overexpressing p53.