The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer

• Verfasst von: Thewes, Verena [VerfasserIn]
• Verfasst von: Schmidt, Karsten [VerfasserIn]
• Verfasst von: Kneisel, Niclas [VerfasserIn]
• Verfasst von: Sinn, Peter [VerfasserIn]
• Verfasst von: Schneeweiss, Andreas [VerfasserIn]
• Verfasst von: Okun, Jürgen G. [VerfasserIn]
• Verfasst von: Lichter, Peter [VerfasserIn]
• Titel: The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer
• Verf.angabe: V. Thewes, R. Simon, M. Hlevnjak, M. Schlotter, P. Schroeter, K. Schmidt, Y. Wu, T. Anzeneder, W. Wang, P. Windisch, M. Kirchgäßner, N. Melling, N. Kneisel, R. Büttner, U. Deuschle, H.P. Sinn, A. Schneeweiss, S. Heck, S. Kaulfuss, H. Hess-Stumpp, J.G. Okun, G. Sauter, A.E. Lykkesfeldt, M. Zapatka, B. Radlwimmer, P. Lichter & M. Tönjes
• E-Jahr: 2017
• Jahr: 20 March 2017
• Umfang: 11 S.
• Fussnoten: Gesehen am 17.04.2018
• Titel Quelle: Enthalten in: Oncogene
• Ort Quelle: London : Springer Nature, 1997
• Jahr Quelle: 2017
• Band/Heft Quelle: 36(2017), 29, Seite 4124-4134
• ISSN Quelle: 1476-5594
• DOI: doi:10.1038/onc.2017.32
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1572098457

Abstract

Antiestrogen-resistant and triple-negative breast tumors pose a serious clinical challenge because of limited treatment options. We assessed global gene expression changes in antiestrogen-sensitive compared with antiestrogen-resistant (two tamoxifen resistant and two fulvestrant resistant) MCF-7 breast cancer cell lines. The branched-chain amino acid transaminase 1 (BCAT1), which catalyzes the first step in the breakdown of branched-chain amino acids, was among the most upregulated transcripts in antiestrogen-resistant cells. Elevated BCAT1 expression was confirmed in relapsed tamoxifen-resistant breast tumor specimens. High intratumoral BCAT1 levels were associated with a reduced relapse-free survival in adjuvant tamoxifen-treated patients and overall survival in unselected patients. On a tissue microarray (n=1421), BCAT1 expression was detectable in 58% of unselected primary breast carcinomas and linked to a higher Ki-67 proliferation index, as well as histological grade. Interestingly, BCAT1 was predominantly expressed in estrogen receptor-α-negative/human epidermal growth factor receptor-2-positive (ERα-negative/HER-2-positive) and triple-negative breast cancers in independent patient cohorts. The inverse relationship between BCAT1 and ERα was corroborated in various breast cancer cell lines and pharmacological long-term depletion of ERα induced BCAT1 expression in vitro. Mechanistically, BCAT1 indirectly controlled expression of the cell cycle inhibitor p27Kip1 thereby affecting pRB. Correspondingly, phenotypic analyses using a lentiviral-mediated BCAT1 short hairpin RNA knockdown revealed that BCAT1 sustains proliferation in addition to migration and invasion and that its overexpression enhanced the capacity of antiestrogen-sensitive cells to grow in the presence of antiestrogens. Importantly, silencing of BCAT1 in an orthotopic triple-negative xenograft model resulted in a massive reduction of tumor volume in vivo, supporting our findings that BCAT1 is necessary for the growth of hormone-independent breast tumors.