The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer.
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 p27Kip1thereby 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.
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
V
V
Thewes
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
R
R
Simon
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
M
M
Hlevnjak
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
M
M
Schlotter
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
P
P
Schroeter
Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
K
K
Schmidt
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Y
Y
Wu
PATH Foundation Biobank-Patients' Tumor Bank of Hope, Munich, Germany.
T
T
Anzeneder
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
W
W
Wang
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
P
P
Windisch
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
M
M
Kirchgäßner
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
N
N
Melling
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
N
N
Kneisel
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
R
R
Büttner
Phenex Pharmaceuticals AG, Heidelberg, Germany.
U
U
Deuschle
Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
H P
HP
Sinn
Gynecologic Oncology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
A
A
Schneeweiss
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
S
S
Heck
Bayer Pharma AG, Berlin, Germany.
S
S
Kaulfuss
Bayer Pharma AG, Berlin, Germany.
H
H
Hess-Stumpp
Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
J G
JG
Okun
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
G
G
Sauter
Breast Cancer Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
A E
AE
Lykkesfeldt
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
M
0000-0001-8287-5967
M
Zapatka
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
B
0000-0002-4553-7800
B
Radlwimmer
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
P
P
Lichter
Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
M
M
Tönjes
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D013629:Tamoxifen / Q000494:pharmacology; D000637:Transaminases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; C490590:BCAT1 protein, human; D000637:Transaminases