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 p27 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.
The effects of the cooperative Jahn-Teller effect on the crystal structure and the stability of the charge ordered (CO) state were studied by measurements of powder X-ray diffraction, resistivity, and ultrasound for Pr 1-x Ca x MnO 3 (0.5≤x≤0.875). Powder X-ray diffraction revealed a change of the crystal structure from tetragonally compressed to tetragonally elongated orthorhombic between x=0.75 and x=0.8 in the CO state, resulting from the crossover of the cooperative Jahn-Teller vibration mode from Q 2 to Q 3 . The relative stiffening of the ultrasound (∆V/V) reflecting the magnitude of the cooperative Jahn-Teller lattice distortion in the CO state increases with increasing x from 0.5 to 0.625, reaching the largest and being almost x-independence for 0.625≤x≤0.8, and drops steeply with further increase of x.Coincident with the variation of the ∆V/V with x, the stability of the CO state reflected by the magnetoresistance effect increases with increasing x from 0.5 to 0.625, reaching the most stable for 0.625
Based on the magnetoresistance, magnetization, ultrasound, and crystallographic data, we studied the role of the cooperative Jahn-Teller effect in the charge ordered (CO) state for La 1-x Ca x MnO 3 . We found that, with increasing the fraction of Q 3 mode of Jahn-Teller distortion and decreasing that of Q 2 mode in the CO state, the magnetic structure evolves from CE-type to C-type and the orbital ordering changes from 2 2 2 2 3 / 3 r y r x d d − − -type to 2 2 3 r z d − -type, with the strength of ferromagnetism and the phase separation tendency being suppressed. At the same time, the stability of the CO state and the cooperative Jahn-Teller lattice distortion increase. These effects imply that the cooperative Jahn-Teller effect with different vibration modes is the key ingredient in understanding the essential physics of the CO state.
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