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

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 -