Gene expression alterations associated with outcome in aromatase inhibitor-treated ER+ early-stage breast cancer patients

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• 作者：Karina G. Thomsen ; Maria B. Lyng ; Daniel Elias…
• 关键词：Breast cancer ; Aromatase inhibitors ; Endocrine resistance ; Estrogen receptor ; Biomarkers ; TFF3
• 刊名：Breast Cancer Research and Treatment
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：154
• 期：3
• 页码：483-494
• 全文大小：1,089 KB
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• 作者单位：Karina G. Thomsen (1)
  Maria B. Lyng (1)
  Daniel Elias (1)
  Henriette Vever (1)
  Ann S. Knoop (2)
  Anne E. Lykkesfeldt (3)
  Anne-Vibeke L?nkholm (4)
  Henrik J. Ditzel (1) (5)
  
  1. Institute of Molecular Medicine, Department of Cancer and Inflammation Research, University of Southern Denmark, J. B. Winslowsvej 25, 5000, Odense, Denmark
  2. Department of Oncology, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark
  3. Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, 2100, Copenhagen, Denmark
  4. Department of Pathology, Slagelse Hospital, 4200, Slagelse, Denmark
  5. Department of Oncology, Odense University Hospital, 5000, Odense, Denmark
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  
• 出版者：Springer Netherlands
• ISSN：1573-7217

文摘

Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor-positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow-up 6.7 years). Gene expression alterations were validated by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change ?.5, p < 0.05), and the gene expression alterations were confirmed using qRT-PCR. Ten of these 26 genes could be linked in a network associated with cellular proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen resistance and metastasis of ER+ breast cancer, was also shown to be upregulated in an AI-resistant cell line model, and reduction of TFF3 levels using TFF3-specific siRNAs decreased the growth of both the AI-resistant and -sensitive parental cell lines. Moreover, overexpression of TFF3 in parental AI-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to the AI exemestane, whereas TFF3 overexpression had no effect on growth in the absence of exemestane, indicating that TFF3 mediates growth and survival signals that abrogate the growth inhibitory effect of exemestane. We identified a panel of 26 genes exhibiting altered expression associated with disease recurrence in patients treated with adjuvant AI monotherapy, including TFF3, which was shown to exhibit a growth- and survival-promoting effect in the context of AI treatment. Keywords Breast cancer Aromatase inhibitors Endocrine resistance Estrogen receptor Biomarkers TFF3