Thewes, V., Simon, R., Hlevnjak, M., Schlotter, M., Schroeter, P., Schmidt, K., Wu, Y., Anzeneder, T., Wang, W., Windisch, P., Kirchgaessner, M., Melling, N., Kneisel, N., Buettner, R., Deuschle, U., Sinn, H. P., Schneeweiss, A., Heck, S., Kaulfuss, S., Hess-Stumpp, H., Okun, J. G., Sauter, G., Lykkesfeldt, A. E., Zapatka, M., Radlwimmer, B., Lichter, P. and Toenjes, M. (2017). The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ER alpha-negative breast cancer. Oncogene, 36 (29). S. 4124 - 4135. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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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-a-negative/human epidermal growth factor receptor-2-positive (ER alpha-negative/HER-2- positive) and triple-negative breast cancers in independent patient cohorts. The inverse relationship between BCAT1 and ER alpha was corroborated in various breast cancer cell lines and pharmacological long-term depletion of ERa induced BCAT1 expression in vitro. Mechanistically, BCAT1 indirectly controlled expression of the cell cycle inhibitor p27(Kip1) 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Thewes, V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hlevnjak, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlotter, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeter, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anzeneder, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Windisch, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirchgaessner, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Melling, N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kneisel, N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deuschle, U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sinn, H. P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneeweiss, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heck, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaulfuss, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hess-Stumpp, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Okun, J. G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sauter, G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lykkesfeldt, A. E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zapatka, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radlwimmer, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lichter, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toenjes, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-224848
DOI: 10.1038/onc.2017.32
Journal or Publication Title: Oncogene
Volume: 36
Number: 29
Page Range: S. 4124 - 4135
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5594
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TAMOXIFEN RESISTANCE; CELL-LINES; EXPRESSION; ESTROGEN; AMINOTRANSFERASE; PROLIFERATION; GENES; MICROARRAYS; ACTIVATION; SIGNATURESMultiple languages
Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22484

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