| Autor: |
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 |
| Zdroj: |
Oncogene; July 2017, Vol. 36 Issue: 29 p4124-4134, 11p |
| Abstrakt: |
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 BCAT1expression 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. |
| Databáze: |
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