title: Tamoxifen downregulates ets oncogene family members ETV4 and ETV5 in benign breast tissue: implications for durable risk reduction.
abstract: Five years of tamoxifen reduces breast cancer risk by nearly 50% but is associated with significant side effects and toxicities. A better understanding of the direct and indirect effects of tamoxifen in benign breast tissue could elucidate new mechanisms of breast carcinogenesis, suggest novel chemoprevention targets, and provide relevant early response biomarkers for phase II prevention trials. Seventy-three women at increased risk for breast cancer were randomized to tamoxifen (20 mg daily) or placebo for 3 months. Blood and breast tissue samples were collected at baseline and posttreatment. Sixty-nine women completed all study activities (37 tamoxifen and 32 placebo). The selected biomarkers focused on estradiol and IGFs in the blood; DNA methylation and cytology in random periareolar fine-needle aspirates; and tissue morphometry, proliferation, apoptosis, and gene expression (microarray and reverse transcriptase PCR) in the tissue core samples. Tamoxifen downregulated Ets oncogene transcription factor family members ETV4 and ETV5 and reduced breast epithelial cell proliferation independent of CYP2D6 genotypes or effects on estradiol, ESR1, or IGFs. Reduction in proliferation was correlated with downregulation of ETV4 and DNAJC12. Tamoxifen reduced the expression of ETV4- and ETV5-regulated genes implicated in epithelial-stromal interaction and tissue remodeling. Three months of tamoxifen did not affect breast tissue composition, cytologic atypia, preneoplasia, or apoptosis. A plausible mechanism for the chemopreventive effects of tamoxifen is restriction of lobular expansion into stroma through downregulation of ETV4 and ETV5. The human equivalent of murine multipotential progenitor cap cells of terminal end buds may be the primary target.
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA. david.euhus@utsouthwestern.edu
authors.forename: David
authors.initials: D
authors.lastname: Euhus
authors.forename: Dawei
authors.initials: D
authors.lastname: Bu
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.forename: Venetia
authors.initials: V
authors.lastname: Sarode
authors.forename: Raheela
authors.initials: R
authors.lastname: Ashfaq
authors.forename: Kelly
authors.initials: K
authors.lastname: Hunt
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Joyce
authors.initials: J
authors.lastname: O'Shaughnessy
authors.forename: Michael
authors.initials: M
authors.lastname: Grant
authors.forename: Banu
authors.initials: B
authors.lastname: Arun
authors.forename: William
authors.initials: W
authors.lastname: Dooley
authors.forename: Alexander
authors.initials: A
authors.lastname: Miller
authors.forename: David
authors.initials: D
authors.lastname: Flockhart
authors.forename: Cheryl
authors.initials: C
authors.lastname: Lewis
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D044963:Biopsy, Fine-Needle; D001940:Breast / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004311:Double-Blind Method; D015536:Down-Regulation; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011230:Precancerous Conditions / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D040242:Risk Reduction Behavior; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use; D013629:Tamoxifen / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D017500:Adenovirus E1A Proteins; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C079853:ETV4 protein, human; C086680:ETV5 protein, human; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D020845:Selective Estrogen Receptor Modulators; D014157:Transcription Factors; D013629:Tamoxifen