The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer
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The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer. / Thewes, V; Simon, R; Hlevnjak, M; Schlotter, M; Schroeter, P; Schmidt, K; Wu, Y; Anzeneder, T; Wang, W; Windisch, P; Kirchgäßner, M; Melling, N; Kneisel, N; Büttner, 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; Tönjes, M.
in: ONCOGENE, Jahrgang 36, Nr. 29, 20.07.2017, S. 4124-4134.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer
AU - Thewes, V
AU - Simon, R
AU - Hlevnjak, M
AU - Schlotter, M
AU - Schroeter, P
AU - Schmidt, K
AU - Wu, Y
AU - Anzeneder, T
AU - Wang, W
AU - Windisch, P
AU - Kirchgäßner, M
AU - Melling, N
AU - Kneisel, N
AU - Büttner, R
AU - Deuschle, U
AU - Sinn, H P
AU - Schneeweiss, A
AU - Heck, S
AU - Kaulfuss, S
AU - Hess-Stumpp, H
AU - Okun, J G
AU - Sauter, G
AU - Lykkesfeldt, A E
AU - Zapatka, M
AU - Radlwimmer, B
AU - Lichter, P
AU - Tönjes, M
PY - 2017/7/20
Y1 - 2017/7/20
N2 - 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.
AB - 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.
KW - Animals
KW - Breast Neoplasms
KW - Cell Line, Tumor
KW - Cell Movement
KW - Cell Proliferation
KW - Drug Resistance, Neoplasm
KW - Estrogen Antagonists
KW - Estrogen Receptor alpha
KW - Female
KW - Gene Expression Profiling
KW - Heterografts
KW - Humans
KW - MCF-7 Cells
KW - Mice
KW - Mice, Inbred BALB C
KW - Tamoxifen
KW - Transaminases
KW - Up-Regulation
KW - Journal Article
U2 - 10.1038/onc.2017.32
DO - 10.1038/onc.2017.32
M3 - SCORING: Journal article
C2 - 28319069
VL - 36
SP - 4124
EP - 4134
JO - ONCOGENE
JF - ONCOGENE
SN - 0950-9232
IS - 29
ER -