The valence shell excitations of argon were investigated by an angle-resolved fast-electron energy-loss spectrometer at an incident electron energy of 2500 eV, and the transition multipolarities for the excitations of 3p → 3d, 4d, 5s, and 5p were elucidated with the help of the calculated intermediate coupling coefficients using the COWAN code. The generalized oscillator strengths for the excitations to 3p 5 ͑3d ,3dЈ͒, 3p 5 ͑5p ,5pЈ͒, and 3p 5 ͑5s ,4d͒ were measured, and the profiles of these generalized oscillator strength were analyzed. Furthermore, although the present experimental positions of the maxima for the electric-monopole and electricquadrupole excitations in 3p → 5p are in agreement with the theoretical calculations ͓Amusia et al., Phys. Rev. A 67, 022703 ͑2003͔͒, the generalized oscillator strength profiles show obvious differences. In addition, the experimental generalized oscillator strength ratios for the electric-octupole transitions in 3p → 3d are different from the theoretical prediction calculated by the COWAN code.
Resistance to chemotherapy remains a major obstacle to the successful treatment of breast cancer. More than 80% of patients who receive neoadjuvant chemotherapy (NAC) do not achieve a pathological complete response. In this study, we report a novel p62 mRNA isoform with a short 3′-UTR (p62-SU, 662-nt) that is associated with chemoresistance in breast cancer cells and tissue specimens. The p62 mRNA isoform was identified by RNA sequencing with qRT-PCR, 3′-RACE, and northern blot analysis. In vitro and in vivo, ectopic expression of p62-SU promoted breast cancer cell proliferation, migration, invasion, and chemoresistance compared with the p62 mRNA isoform with a full-length 3′-UTR (p62-LU, 1,485-nt). Mechanistically, CPSF1 modulated the 3′-UTR of p62 through alternative polyadenylation. In addition, p62-SU escaped miR-124-3p-mediated repression and upregulated p62-SU protein expression, thereby inducing p62-dependent chemoresistance. These data suggest that a CPSF1-p62-miR-124-3p signaling axis is responsible for reduced sensitivity of breast cancer to chemotherapy.
Estrogen receptor alpha (ERα) plays a vital role in the development of normal breast tissue and in breast cancer. By cross-analyzing The Cancer Genome Atlas (TCGA) database, ERα-regulated long noncoding RNA 1 (ERLC1) was identified as a long noncoding RNA exhibiting a strong association with ERα signaling and high specificity of expression in breast tissue. ERLC1 was transcriptionally activated by ERα, and ERLC1 stabilized the ESR1 transcript by sequestering miR-129 and tethering FXR1 to maintain a positive feedback loop that potentiated ERα signaling. ERLC1 was elevated in tamoxifen-resistant breast cancer cells, where ERLC1 depletion restored sensitivity to tamoxifen and increased the efficacy of palbociclib or fulvestrant therapy. Collectively, these data warrant further investigation of ERLC1 as a modulator of therapeutic response and potential therapeutic target in ER+ breast cancer.
Significance:
This study identifies an estrogen-regulated lncRNA and the mechanism by which it positively regulates ERα activity, demonstrating a feedback loop that can promote resistance to antiestrogen therapies in ER+ breast cancer.
<div>Abstract<p>Resistance to chemotherapy remains a major obstacle to the successful treatment of breast cancer. More than 80% of patients who receive neoadjuvant chemotherapy (NAC) do not achieve a pathologic complete response. In this study, we report a novel p62 mRNA isoform with a short 3′-UTR (untranslated region; p62-SU, 662-nt) that is associated with chemoresistance in breast cancer cells and tissue specimens. The p62 mRNA isoform was identified by RNA sequencing with qRT-PCR, 3′-RACE, and Northern blot analysis. <i>In vitro</i> and <i>in vivo</i>, ectopic expression of p62-SU promoted breast cancer cell proliferation, migration, invasion, and chemoresistance compared with the p62 mRNA isoform with a full-length 3′-UTR (p62-LU, 1,485-nt). Mechanistically, cleavage and polyadenylation specific factor 1 (CPSF1) modulated the 3′-UTR of p62 through alternative polyadenylation. In addition, p62-SU escaped miR-124-3p–mediated repression and upregulated p62-SU protein expression, thereby inducing p62-dependent chemoresistance. These data suggest that a CPSF1-p62-miR-124-3p signaling axis is responsible for reduced sensitivity of breast cancer to chemotherapy.</p>Significance:<p>Resistance to NAC in breast cancer is driven by a novel p62 mRNA isoform that escapes miRNA-mediated repression and leads to increased p62 protein expression.</p></div>
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