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Tamoxifen downregulates ets oncogene family members ETV4 and ETV5 in benign breast tissue: implications for durable risk reduction
Journal article   Open access   Peer reviewed

Tamoxifen downregulates ets oncogene family members ETV4 and ETV5 in benign breast tissue: implications for durable risk reduction

David Euhus, Dawei Bu, Xian-Jin Xie, Venetia Sarode, Raheela Ashfaq, Kelly Hunt, Weiya Xia, Joyce O'Shaughnessy, Michael Grant, Banu Arun, …
Cancer prevention research (Philadelphia, Pa.), Vol.4(11), pp.1852-1862
11/2011
DOI: 10.1158/1940-6207.CAPR-11-0186
PMCID: PMC3208724
PMID: 21778330
url
https://doi.org/10.1158/1940-6207.CAPR-11-0186View
Published (Version of record) Open Access

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.
 Carcinoma, Lobular - pathology Prospective Studies Follow-Up Studies Oligonucleotide Array Sequence Analysis Apoptosis - drug effects Humans Middle Aged Male Precancerous Conditions - metabolism Gene Expression Profiling Breast - metabolism Breast Neoplasms - metabolism DNA-Binding Proteins - metabolism Precancerous Conditions - drug therapy Selective Estrogen Receptor Modulators - therapeutic use Adenovirus E1A Proteins - metabolism Aged, 80 and over Biomarkers, Tumor - metabolism Adult Female Precancerous Conditions - pathology Breast - pathology Proto-Oncogene Proteins - metabolism Double-Blind Method Risk Reduction Behavior Down-Regulation Proto-Oncogene Proteins - genetics Treatment Outcome Transcription Factors - genetics DNA-Binding Proteins - genetics Breast Neoplasms - drug therapy Transcription Factors - metabolism Biopsy, Fine-Needle Breast - drug effects Breast Neoplasms - pathology Adenovirus E1A Proteins - genetics Tamoxifen - therapeutic use Aged Biomarkers, Tumor - genetics Carcinoma, Lobular - drug therapy Carcinoma, Lobular - metabolism Cell Proliferation - drug effects Neoplasm Staging DNA Methylation - drug effects

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