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.

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

“…The study was fueled by previous observations that in ER-positive breast cancer responding to endocrine treatment, AR downregulation at the protein and mRNA level is observed, whereas no such effect is seen in nonresponsive tumors (56,57). In a cohort of 192 patients with earlystage ER-positive breast cancer receiving adjuvant tamoxifen treatment and another one of a randomized phase II trial assessing exemestane with or without tamoxifen, high AR:ER ratio was found to predict resistance to endocrine therapy in a statistically significant manner.…”

Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer

“…AIs block the conversion of androgen to estrogen, thus increasing free testosterone and DHEA-S [70]. Previous studies have shown that patients with ER positive tumors that are responders to neoadjuvant AI therapy, display decreased AR mRNA and nuclear protein, while non-responders continue to have elevated AR expression [71, 72]. Our data are in accordance with previous reports that AR overexpression in breast cancer cell lines leads to tamoxifen and AI resistance [65, 73].…”

Gene expression profiling and prediction of response to hormonal neoadjuvant treatment with anastrozole in surgically resectable breast cancer

“…and ER-) patients, defining only a group of differentially expressed genes between partial response and progressive disease. Harvell et al [13] used exemestane, alone or in combination with tamoxifen, on 7 ER? breast cancers and individuated 50 genes associated with response; however, treatment of the 7 patients was not homogeneous: all responders were treated with exemestane only, but among non responders, three were treated with the two drugs in combination and one received exemestane only.…”

“…Signatures correlated to response to neoadjuvant treatment have been also identified for exemestane, although on a very small patient cohort, and letrozole [13,14]. Our goals were to (i) examine changes in gene expression with anastrozole therapy and (ii) identify genetic signatures that might distinguish between ER?…”