Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Thewes, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Simon, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hlevnjak, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlotter, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeter, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wu, Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Anzeneder, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Windisch, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirchgaessner, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Melling, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kneisel, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Deuschle, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sinn, H. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneeweiss, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heck, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaulfuss, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hess-Stumpp, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Okun, J. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sauter, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lykkesfeldt, A. E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zapatka, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Radlwimmer, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lichter, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Toenjes, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language TAMOXIFEN RESISTANCE; CELL-LINES; EXPRESSION; ESTROGEN; AMINOTRANSFERASE; PROLIFERATION; GENES; MICROARRAYS; ACTIVATION; SIGNATURES Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22484