title: Estrogen regulated gene expression in response to neoadjuvant endocrine therapy of breast cancers: tamoxifen agonist effects dominate in the presence of an aromatase inhibitor.
abstract: Estrogens (E) and estrogen receptors (ER) are implicated in breast cancer growth and are targets of hormonal therapies. Such therapies commonly use aromatase inhibitors (AI) to block E production, or antiestrogens like tamoxifen (TAM), which targets ER. Here we compare genes in pre-and post-treatment tumor pairs of patients with ER+ tumors, that were treated preoperatively with the AI exemestane alone, or with exemestane plus TAM. The accompanying manuscript shows that tumors from patients treated with AI + TAM responded less well than tumors treated with AI alone. The present manuscript defines the E-signaling mechanisms underlying these differences, and describes genetic differences between hormone responsive versus intrinsically resistant ER+ tumors. Gene expression profiling was performed on paired tumor biopsies of individual patients before treatment, and after 4 months of treatment with AI or AI + TAM. Separately, E and TAM regulated genes were defined using a human breast cancer xenograft model. We demonstrate: (1) that AI alone alters global gene expression approximately 5 times more than AI + TAM, and is 11 times more effective in modifying expression of E regulated genes; (2) among E regulated genes, there is little overlap between AI and AI + TAM treatment groups. AI + TAM preferentially induce genes, like androgen receptors, expressing TAM "E-like" agonist activity, or genes uniquely regulated by TAM. (3) A pre-treatment 25 gene signature of ER+ tumors may predict response or intrinsic resistance to endocrine therapies. We conclude that in the presence of exemestane, the agonist properties of TAM are paradoxically exposed, diminishing the effectiveness of combination therapy.
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences Center at Fitzsimons, Aurora, CO 80045, USA. djuana.harvell@uchsc.edu
authors.forename: Djuana M E
authors.initials: DM
authors.lastname: Harvell
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Richer
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Singh
authors.forename: Nicole
authors.initials: N
authors.lastname: Spoelstra
authors.forename: Christina
authors.initials: C
authors.lastname: Finlayson
authors.forename: Virginia F
authors.initials: VF
authors.lastname: Borges
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Elias
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Horwitz
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D011960:Receptors, Estrogen; D013629:Tamoxifen; C056516:exemestane