[Chemoprevention of Breast Cancer-Risk Reduction of Onset by Hormonal Agents].

Since estrogen is essential for the development of breast cancer, hormonal agents are used for breast cancer prevention. Clinical trials with selective estrogen receptor modifiers and aromatase inhibitors(AI)have shown that tamoxifen is the most promising breast cancer chemopreventive agent, but the use of raloxifene must be considered due to adverse events. AI has also proven to be a chemopreventive agent for postmenopausal women. Because chemical prevention carries the risk of adverse events and target's healthy women, it is essential to assess the onset risk to confirm the need for prophylactic administration. However, all current evidence was born in clinical trials for Western's but not for Japanese. Also, the risk assessment tools of breast cancer used was all based on Western data. Therefore, the recommended chemoprevention in the Western countries is still difficult to say as the standard therapy for Japanese women. Today, breast cancer in Japanese women is explosively increasing. Under these circumstances, establishment of assessment tools for onset risk and chemoprevention methods for Japanese women is a pressing issue.

Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2.

Natural products have numerous bioactivities and are expected to be a resource for potent drugs. However, their direct targets in cells often remain unclear. We found that rabdosianone I, which is a bitter diterpene from an oriental herb for longevity, Isodon japonicus Hara, markedly inhibited the growth of human colorectal cancer cells by downregulating the expression of thymidylate synthase (TS). Next, using rabdosianone I-immobilized nano-magnetic beads, we identified two mitochondrial inner membrane proteins, adenine nucleotide translocase 2 (ANT2) and prohibitin 2 (PHB2), as direct targets of rabdosianone I. Consistent with the action of rabdosianone I, the depletion of ANT2 or PHB2 reduced TS expression in a different manner. The knockdown of ANT2 or PHB2 promoted proteasomal degradation of TS protein, whereas that of not ANT2 but PHB2 reduced TS mRNA levels. Thus, our study reveals the ANT2- and PHB2-mediated pleiotropic regulation of TS expression and demonstrates the possibility of rabdosianone I as a lead compound of TS suppressor.

Deactivation of Glutaminolysis Sensitizes PIK3CA-Mutated Colorectal Cancer Cells to Aspirin-Induced Growth Inhibition.

Aspirin is one of the most promising over-the-counter drugs to repurpose for cancer treatment. In particular, aspirin has been reported to be effective against PIK3CA-mutated colorectal cancer (CRC); however, little information is available on how the PIK3CA gene status affects its efficacy. We found that the growth inhibitory effects of aspirin were impaired upon glutamine deprivation in PIK3CA-mutated CRC cells. Notably, glutamine dependency of aspirin-mediated growth inhibition was observed in PIK3CA-mutated cells but not PIK3CA wild type cells. Mechanistically, aspirin induced G1 arrest in PIK3CA-mutated CRC cells and inhibited the mTOR pathway, inducing the same phenotypes as glutamine deprivation. Moreover, our study including bioinformatic approaches revealed that aspirin increased the expression levels of glutaminolysis-related genes with upregulation of activating transcription factor 4 (ATF4) in PIK3CA-mutated CRC cells. Lastly, the agents targeting glutaminolysis demonstrated significant combined effects with aspirin on PIK3CA-mutated CRC cells. Thus, these findings not only suggest the correlation among aspirin efficacy, PIK3CA mutation and glutamine metabolism, but also the rational combinatorial treatments of aspirin with glutaminolysis-targeting agents against PIK3CA-mutated CRC.

[Effectiveness of Strontium-89 for Neuropathic Pain Caused by Bone Metastases from Breast Cancer: A Case Report].

The patient was a 47-year-old female with stage IV breast cancer and multiple bone metastases. She received various systemic therapies (hormone therapy and chemotherapy) and underwent mastectomy between 2013 and 2018; in the beginning of 2018, she started experiencing bone metastatic pain in the right hip joint and neural pain on the dorsal side of the left thigh. These symptoms worsened gradually, and nonsteroidal anti-inflammatory analgesics or narcotic analgesics were not effective for treating this pain. Strontium-89 (89Sr) treatment was administered in April 2018. The pain was relieved immediately after 89Sr treatment. The patient's quality of life improved markedly. She spent her remaining life without using analgesic drugs, until she died in October 2018 due to exacerbation of the original disease. Although radiotherapy is believed to be less effective for neuropathic pain than for bone metastatic pain, it should be considered as a treatment option in patients with neuropathic pain.

Mevalonate pathway blockage enhances the efficacy of mTOR inhibitors with the activation of retinoblastoma protein in renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common malignancy of kidney and remains largely intractable once it recurs after resection. mTOR inhibitors have been one of the mainstays used against recurrent RCC; however, there has been a major problem of the resistance to mTOR inhibitors, and thus new combination treatments with mTOR inhibitors are required. We here retrospectively showed that regular use of antilipidemic drug statins could provide a longer progression free survival (PFS) in RCC patients prescribed with an mTOR inhibitor everolimus than without statins (median PFS, 7.5 months vs. 3.2 months, respectively; hazard ratio, 0.52; 95% CI, 0.22-1.11). In order to give a rationale for this finding, we used RCC cell lines and showed the combinatorial effects of an mTOR inhibitor with statins induced a robust activation of retinoblastoma protein, whose mechanisms were involved in statins-mediated hindrance of KRAS or Rac1 protein prenylation. Finally, statins treatment also enhanced the efficacy of an mTOR inhibitor in RCC xenograft models. Thus, we provide molecular and (pre)clinical data showing that statins use could be a drug repositioning for RCC patients to enhance the efficacy of mTOR inhibitors.

Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells.

With increasing clinical demands for MEK inhibitors in cancer treatment, overcoming the resistance to MEK inhibitors is an urgent problem to be solved. Numerous reports have shown that MEK inhibition results in the activation of PI3K-Akt signaling, which may confer apoptotic resistance to MEK inhibitors. We here demonstrate that the blockade of the mevalonate pathway using the antilipidemic drug statins represses Akt activation following MEK inhibition and induces significant apoptosis when co-treated with CH5126766 or trametinib. These events were clearly negated by the addition of mevalonate or geranylgeranyl pyrophosphate, indicating that the protein geranylgeranylation is implicated in the apoptotic resistance to MEK inhibitors. Furthermore, mechanistically, the combined treatment of CH5126766 with statins upregulated TNF-related apoptosis-inducing ligand (TRAIL), which was dependent on inhibition of the mevalonate pathway and is involved in apoptosis induction in human breast cancer MDA-MB-231 cells. The present study not only revealed that the mevalonate pathway could be targetable to enhance the efficacy of MEK inhibitors, but also proposes that combinatorial treatment of MEK inhibitors with statins may be a promising therapeutic strategy to sensitize cancer cells to apoptosis.

[Long-term complete response in a patient with breast cancer and bone and pleura metastases after treatment with a combination of S-1 and zoledronic acid].

We report a long-term complete response (CR) in a patient with postoperative recurrent breast cancer and bone and pleura metastases after treatment with a combination of S-1 and zoledronic acid. We administered 4 courses of tri-weekly CE (epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2) and 12 courses of weekly paclitaxel (80 mg/m2) as adjuvant chemotherapy. However, combination therapy with S-1 and zoledronic acid was started because of the development of bone and pleura metastases. S-1 was administered orally at 100 mg/day everyday for 2 weeks, followed by a 1-week rest interval as 1 course; 4 mg of zoledronic acid was injected every 4 weeks. After 3 cycles of treatment, the patient's tumor marker levels had decreased to normal values, and both the bone and pleura metastases had disappeared. A long-term complete response was obtained as a result of this combination therapy.

Clinical outcomes of video-assisted skin-sparing partial mastectomy for breast cancer and immediate reconstruction with latissimus dorsi muscle flap as breast-conserving therapy.

BACKGROUND: Skin-sparing partial mastectomy (SSPM) has yet to be investigated as a breast-conserving therapy for early-stage breast cancer. We report the clinical outcomes for video-assisted SSPM (VA-SSPM) with immediate breast reconstruction using autogenous tissue. METHODS: VA-SSPM is indicated for early-stage breast cancer arising in the upper-outer or lower-outer quadrant without skin involvement. An incision is placed along the midaxillary line, and SSPM is performed under endoscopic guidance using subcutaneous tunneling and lifting methods. Through the same incision, a latissimus dorsi muscle flap is harvested for breast reconstruction. From January 2000 to October 2007, 168 patients (Tis, n = 24; T1, n = 37; T2, n = 107) underwent VA-SSPM, and morbidity, curability, and postoperative patient satisfaction were investigated. RESULTS: Postoperative complications included skin necrosis (2.4%, n = 4) and muscle flap necrosis (0.6%, n = 1), but no severe complications were observed. After a mean follow-up of 58.6 months, eight patients (4.8%) experienced local recurrence. Sixty-month distant metastasis-free survival rates for Tis, T1, and T2 were 100%, 97%, and 83.3%, respectively, with an overall rate of 88.4%. Furthermore, overall survival rates for Tis, T1, and T2 were 100%, 94.1%, and 94.4%, respectively, with an overall survival rate of 95% for all patients. A patient satisfaction survey showed that 81.6% of patients evaluated the surgery as "good." CONCLUSIONS: VA-SSPM for early-stage breast cancer improves cosmetic results and achieves high patient satisfaction without increasing local or distant organ recurrence. This method offers a useful local therapy for early-stage breast cancer.