Takafumi Ujihira

Proteasome 26S subunit PSMD1 regulates breast cancer cell growth through p53 protein degradation

Endocrine therapy using antiestrogens and aromatase inhibitors is usually efficient to treat patients with hormone-sensitive breast cancer. Many patients with endocrine therapy, however, often acquire resistance. In the present study, we performed functional screening using short hairpin RNA library to dissect genes involved in antiestrogen tamoxifen resistance in MCF-7 breast cancer cells. We identified seven candidate genes that are associated with poor prognosis of breast cancer patients based on clinical dataset. The expression levels of six out of seven genes were higher in 4-hydroxytamoxifen (OHT) resistant MCF-7 (OHTR) cells compared with parental MCF-7 cells. Among the six selected genes, siRNA-mediated knockdown of PSMD1 and TSPAN12 markedly reduced the proliferation of OHTR cells. Notably, the knockdown of proteasome 26S subunit PSMD1 exhibited cell cycle arrest and the accumulation of p53 protein through inhibiting p53 protein degradation. In accordance with p53 accumulation, its target genes p21 and SFN were also upregulated by PSMD1 silencing. Taken together, PSMD1 was identified as a potential gene that plays a role in the development of tamoxifen resistance in breast cancer cells. These findings will provide a new insight for the mechanism underlying endocrine therapy resistance and a prognostic and therapeutic molecular target for advanced breast cancer.

A phase II randomised study to evaluate the efficacy of aprepitant plus palonosetron for preventing delayed‐phase CINV associated with TC therapy in gynaecological cancer

Chemotherapy‐induced nausea and vomiting (CINV) is one of the most frequently encountered side effects of cancer treatment. Severe CINV can lead patients to refuse chemotherapy, which ultimately affects cancer outcomes. The development of fairly new antiemetic agents, 5‐hydroxytryptamine‐3 receptor antagonists, palonosetron and neurokinin‐1 receptor antagonists and aprepitant has reduced the risk and incidence of CINV. In this study, we assessed the efficacy of aprepitant plus palonosetron against palonosetron for CINV in patients receiving moderately emetic cancer chemotherapy (paclitaxel and carboplatin combination [TC] therapy).

Outcome of Neoadjuvant Intra-Arterial Chemotherapy and Radical Hysterectomy for Treatment of Bulky Stage IB to Stage IIB Uterine Cervical Cancer: Can Postoperative Irradiation Be Avoided?

Objectives We evaluated whether our neoadjuvant intra-arterial chemotherapy (NAIC) effectively precludes the need for postoperative radiation therapy in patients treated by radical hysterectomy for IB2 to IIB cervical cancer. Materials and Methods Study subjects were 52 patients with a bulky cervical tumor diagnosed and treated at Juntendo University Hospital or Juntendo Nerima Hospital. The NAIC combined cisplatin, epirubicin, mitomycin-C, and 5-fluorouracil; and radical hysterectomy was to be performed after 2 cycles. The main variables analyzed were clinical and histologic response to NAIC, NAIC-related adverse events, adjuvant chemotherapies, relapse-free and overall survival, recurrence, and prognostic factors. Results Patients were judged eligible for radical hysterectomy, and 51 underwent the surgery. The overall positive response (complete response [CR] + partial response [PR]) to NAIC was 88.5%. Median follow-up time was 84 months (5–136 months). Three-year relapse-free survival and overall survival were 80.5% and 77.8%, respectively. The recurrence rate was 19.2% (10/52 patients). Seven (13.5%) of the 52 patients died from the disease during follow-up. Lymph node status (positive vs negative) and the histologic effect of NAIC (grades 0–1 vs grades 2–3) were shown to be prognostic factors (P = 0.024 and P = 0.021, respectively). Conclusions Our NAIC strategy seems to be well tolerated and beneficial for patients with bulky IB2 to IIB cervical cancer. With this strategy, radiation therapy remains an option in cases of recurrence. For cases in which lymph node metastasis is found or the histologic effect of NAIC is low, our adjuvant chemotherapy regimen may need adjustment to improve prognosis.