Abstract
Abstract Background: Cross-talk between estrogen receptor (ER) and growth factor signaling pathways has been suggested to play a role in development of resistance to endocrine treatment with tamoxifen or aromatase inhibitors (AIs). While HER-2/neu amplification has been associated with lack of endocrine sensitivity in ER+ breast cancer, recent data have suggestedanti-HER-2 therapy to enhance efficacy of AIs in a subset of HER-2/neu non-amplified breast cancers [1], and we found HER-2/neu upregulation in tumors responding to therapy with AIs [2]. Here, we aimed at exploring the effect of treatment with AIs on other components of the HER family, including NRG1, recently reported to be subject to silencing through promoter methylation in breast cancers [3]. Methods: Tumor biopsies were collected from 60 ER + breast cancers before and after 3 months treatment with the AIs, Anatrozole or Letrozole. Tumor biopsies after 2 weeks of treatment were available for 39 of the patients. RNA was extracted from the tumors and mRNA expression analysis of HER-1, HER-2/neu, HER-3, HER-4 and NRG1 were performed with gene-specific primers and probes by real-time PCR. Changes in mRNA expression during treatment were analyzed by Wilcoxon Sign Rank tests, and correlation between expression groups by Spearman correlation. Results: Among HER-2/neu non-amplified tumors (n=56), we observed a significant increase in mRNA expression for HER-1 (40/50 tumors; mean increase 2.0-fold) and NRG1 (38/54 tumors; mean increase 2.9-fold) during treatment independent of treatment response (P<0.001 for both). A non-significant increase in Her-2/neu was observed in 28/54 tumors (18/38 responders). Interestingly, individual alterations in tumor HER-2/neu correlated negatively to change in HER-1 (R=-0.414, p=0.001). Data on DNA methylation at the NRG1 gene will be presented. While no statistical significant increase or decrease in HER-3 or -4 were observed, individual variations in these two parameters were statistically correlated among individual tumors (R=0.621, P<0.001). Conclusions: Estrogen suppression with use of AIs significantly increased intratumor expression levels of HER-1 and NRG1 in HER-2/neu non-amplified tumors, while HER-2/neu increased in a subset of tumors. These findings suggest extensive cross-talks between estrogen stimulation and the HER system, indicating potential mechanisms of therapy resistance. The increase in NRG1 during treatment with AIs may represent a cellular response that leads to changes in its tumor suppressor activity. These findings merits further explorations. 1. Johnston, S., et al., Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol, 2009. 27(33): p. 5538-46. 2. Flageng, M.H., et al., Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors. Br J Cancer, 2009. 101(8): p. 1253-60. 3. Chua, Y.L., et al., The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene. Oncogene, 2009. 28(46): p. 4041-52. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-02.
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