Effects of androgen receptor on aromatase expression

2012 Fiscal Year Final Research Report

• Project/Area Number: 22591422
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Gunma University
• Principal Investigator: HORIGUCHI Jun 群馬大学, 大学院・医学系研究科, 准教授 (70272242)
• Co-Investigator(Kenkyū-buntansha): ROKUTANDA Nana 群馬大学, 医学部, 助教 (50420097) ; TOKINIWA Hideaki 群馬大学, 医学部, 助教 (50455979) ; KOIBUCHI Noriyuki 群馬大学, 大学院・医学系研究科, 教授 (80234681) ; IWASAKI Toshiharu 群馬大学, 大学院・医学系研究科, 講師 (80375576)
• Project Period (FY): 2010 – 2012
• Keywords: アロマターゼ / アンドロゲン受容体

Research Abstract

Estrogen is a key regulator of the proliferation and differentiation of breast cancer cells. In addition to the estrogen supply from the ovary, estrogen is produced locally from androgen by aromatase. However, the regulation of aromatase gene expression in breast cancer has not yet been fully clarified.Retinoic acid receptor-related orphan receptor (ROR) alpha plays an important role in the differentiation of many organs by regulating the transcription of target genes. Because aromatase and RORalpha are expressed in breast cancer, the effect of RORalpha on aromatase gene expression was studied. RORalpha significantly augmented the expression of aromatase mRNA, particularly those containing exon I.4, in MCF7 cells, and aromatase activities in T47D and MCF7 cells. RORalpha also stimulated the proliferation of these cells. Transient transfection-based reporter gene assays using the promoter at exon I.4 showed that RORalpha augmented the transcription. A series of truncated mutation studies revealed that RORalpha activated the transcription through -147 to +14 bp of the promoter I.4. Furthermore, RORalpha bound to the fragment containing -119 to -107 bp of the promoter in vitro, indicating that this region may contain a novel ROR response element. Chromatin immunoprecipitation assay showed that RORalpha bound to the region containing this site of the promoter I.4 in MCF7 cells.Moreover, we examined clinical samples and found a correlation between RORalpha and aromatase expression. These results suggest that RORalpha directly activates the aromatase expression to accelerate the local production of estrogen, which results in the proliferation of breast cancer cells.

Research Products

• [Journal Article] 乳癌(第2版)基礎と臨床の最新研究動向、乳癌治療戦略を目指した基礎研究 (2012)
  • Author(s): 小田原広樹、堀口淳
  • Journal Title: 乳癌におけるRORα発現およびGR発現によるアロマターゼ遺伝子抑制日本臨床 Volume: 70 Pages: 213-217
• [Journal Article] Topoisomerase II alpha expression and the Ki-67 labeling index correlate with prognostic factors in estrogenreceptor-positive and human epidermal growth factor type-2-negative breast cancer (2012)
  • Author(s): Tokiniwa H, Horiguchi J, Takata D, Kikuchi M, Rokutanda N, Nagaoka R, Sato A, Odawara H, Tozuka K, Oyama T, Takeyoshi I.
  • Journal Title: Breast Cancer Volume: 19 Pages: 309-14
  • Peer Reviewed
• [Journal Article] Correlation of L-type aminoacid transporter 1 and CD98 expression with triple negative breast cancer prognosis (2012)
  • Author(s): Furuya M, Horiguchi J, Nakajima H, KanaiY, Oyama T
  • Journal Title: Cancer Sci Volume: 103 Pages: 382-389
  • Peer Reviewed
• [Journal Article] Efficacy of zoledronic acid in postmenopausal Japanese women with early breast cancer receiving adjuvant letrozole: 12-month results (2012)
  • Author(s): Takahashi S, Iwase T, Kohno N, Ishikawa T, Taguchi T, Takahashi M, Horiguchi J, Nakamura S, Hozumi Y, Fukunaga M, Noguchi S
  • Journal Title: Breast Cancer Res Treat Volume: 133 Pages: 685-92
  • Peer Reviewed
• [Journal Article] Triple-negative breast cancer: histological subtypes and immunohistochemical and clinicopathological features (2011)
  • Author(s): Ishikawa Y, Horiguchi J, Toya H, Nakajima H, Hayashi M, Tagaya N, Takeyoshi I, Oyama T
  • Journal Title: Cancer Sci Volume: 102 Pages: 656-662
  • Peer Reviewed
• [Journal Article] New trends in primary systemic therapy for breast cancer (2011)
  • Author(s): Horiguchi J
  • Journal Title: Breast Cancer Volume: 18 Pages: 73
• [Journal Article] Papillary lesions of the breast diagnosed using core needle biopsies (2011)
  • Author(s): Tokiniwa H, Horiguchi J, Takata D, Kikuchi M, Rokutanda N, Nagaoka R, Sato A, Odawara H, Tozuka K, Oyama T, Takeyoshi I
  • Journal Title: Experimental Therapeutic Med Volume: 2 Pages: 1069-1072
  • Peer Reviewed
• [Journal Article] Pathological Complete Response and Prognosis in Patients Receiving Neoadjuvant Paclitaxel and Trastuzumab with and without Anthracyclines for Stage II and III, HER2-positive Operable Breast Cancer: A Single-institute Experience (2011)
  • Author(s): Horiguchi J, Oyama T, Takata D, Rokutanda N, Nagaoka R, Odawara H, Tokiniwa H, Tozuka K, Kikuchi M, Sato A,Takeyoshi I
  • Journal Title: Anticancer Res Volume: 31 Pages: 3041-3046
  • Peer Reviewed
• [Presentation] Change of circulating tumor cells before and after neoad juvant chemotherapy in patients with primary breast cancer (2012)
  • Author(s): J. Horiguchi, D. Takata, N. Rokutanda, R. Nagaoka, A. Sato, H. Tokiniwa, K. Tozuka, S. Uchida, M. Kikuchi, T. Oyama, I. Takeyoshi
  • Organizer: San Antonio Breast Cancer Symposium
  • Place of Presentation: サンア ントニオ
  • Year and Date: 20121204-08
• [Presentation] Circulating tumor cells before and after neoadjuvant chemotherapy in patients with primary breast cancer European Breast Cancer Conference 8, 2012. 3 Wien (2012)
  • Author(s): J. Horiguchi, D. Takata, N. Rokutanda, R. Nagaoka, A. Sato, H. Tokiniwa, K. Tozuka, M. Kikuchi, Y. Iino, I. Takeyoshi
  • Organizer: EBCC ポスター発表
  • Place of Presentation: ウィーン
  • Year and Date: 2012-03-23
• [Presentation] Circulating tumor cells in primary and metastatic breast cancer patients (2011)
  • Author(s): Horiguchi J, Takata D, Rokutanda N, Nagaoka R, Sato A, Tokiniwa H, Tozuka K, Kikuchi M, Takeyoshi I
  • Organizer: Grobal Breast Cancer conference
  • Place of Presentation: Seoul, Korea
  • Year and Date: 20111106-08