In Clinical Cancer Research this week, a team in Ireland reports on the activity of the estrogen receptor co-activator protein AIB1 in the development of aromatase inhibitor-resistant breast tumors. Using tissue from breast cancer patients with aromatase inhibitor-resistance and cell line models of resistance, the team found that AIB1 expression is associated with disease recurrence and reduced disease-free survival time in patients treated with an aromatase inhibitor as first-line therapy. "In a cell line model of resistance to letrozole, we found ERα/AIB1 promoter recruitment and subsequent expression of the classic ER target genes pS2 and Myc to be constitutively upregulated in the presence of both androstenedione and letrozole," the authors write. "In contrast, the recruitment of the ERα/AIB1 transcriptional complex to the nonclassic ER target cyclin D1 and its subsequent expression remained sensitive to steroid treatment and could be inhibited by treatment with letrozole."
Also in Clinical Cancer Research this week, investigators in Italy and Germany report that RRM1 gene expression may serve as a marker of efficacy for adjuvant mitotane therapy in adrenocortical cancer. The team studied samples from 92 adrenocortical cancer patients, 54 of whom received surgery alone and 38 of whom received adjuvant mitotane therapy after surgery. They found that high RRM1 gene expression in both groups of patients was associated with shorter disease-free and overall survival. Low RRM1 expression was associated with improved disease-free survival in the patients receiving adjuvant mitotane. "In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells," the authors write. "Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane."
Finally in Clinical Cancer Research this week, researchers in Northern Ireland report that elevated levels of the protein c-FLIP in patients with castration-resistant prostate cancer antagonize therapeutic response to androgen receptor-targeted therapy. The team characterized c-FLIP expression in prostatectomy tissue and found that expression was increased in high-grade prostatic intra-epithelial neoplasia and prostate cancer tissue, compared to normal prostate tissue. In addition, the team detected maximal c-FLIP expression in castration-resistant prostate cancer samples. "In vitro, silencing of c-FLIP induced spontaneous apoptosis," the authors write. "The histone deacetylase inhibitors, droxinostat and SAHA, also down-regulated c-FLIP expression, induced caspase-8 and caspase-3/7 mediated apoptosis and increased apoptosis in bicalutamide-treated cells. … Knockdown of c-FLIP induced spontaneous apoptosis in [prostate cancer] cells, indicating its relevance to cell survival and therapeutic resistance."