Pilot trial of an electronic patient-reported outcome monitoring system in patients with metastatic breast cancer undergoing chemotherapy.

BACKGROUND: Electronic patient-reported outcomes monitoring (ePROM) is a useful communication tool for patients and healthcare providers in cancer chemotherapy. In this study, we examined the feasibility of our newly developed ePROM system, which we refer to as "Hibilog". METHODS: An ePROM app was developed by extracting 18 items from the Patient-Reported Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE). Symptom monitoring was conducted every two weeks for patients with metastatic breast cancer undergoing chemotherapy. The primary outcome was the response rate to the ePROM system. The secondary outcomes were response time, item missing rate, and distribution of responses for each symptom. RESULTS: A total of 71 cases (mean age 52.6 years) were analyzed. Performance status was 0 in 76% of the cases and 1 or higher in 24%. First-line treatment was being administered in 30% of cases, second-line treatment in 17%, and third-line or higher treatment in 53%. The response rate to the ePROM system from registration to week 40 remained high at around 80%, indicating good compliance. The average response time was 5.5 min and the missing rate for each item was below 0.4%. Among 1,093 responses, the top 3 symptoms causing interference with daily life were Fatigue (63%), Numbness and tingling (48%), and General pain (46%). CONCLUSION: Our developed ePROM system was able to capture symptoms accurately in patients with metastatic breast cancer undergoing chemotherapy while maintaining a high response compliance.

[Three Cases of Orbital Metastasis from Breast Cancer Treated with Radiotherapy].

Orbital metastasis from breast cancer is relatively uncommon and is not the dominant prognosis. While it can reduce a patient's QOL through symptoms such as diplopia, visual impairment, and exophthalmos, evidence suggests that radiotherapy might improve these symptoms in a relatively short period. We report 3 cases of orbital metastasis from breast cancer treated with radiotherapy. All 3 patients were diagnosed with stage Ⅳ breast cancer and underwent chemotherapy and endocrine therapy for several years. When they were diagnosed with orbital metastasis, their life expectancy was only a few months with debilitating illness. They received radiotherapy, which caused slight side effects including skin disorders. The cancer symptoms rapidly improved in 2 patients, suggesting that radiotherapy can be an efficacious choice for improving the QOL for patients with orbital metastasis from breast cancer, especially for patients in terminal status.

A case report of fibroadenoma of the breast with characteristic cystic change on a cut surface.

Fibroadenoma with remarkable cystic change is very unusual. Opinions differ as to the interpretation of this lesion. Furthermore, there have been few reports focusing on its macroscopic view. We herein report a case of fibroadenoma in a 43-year-old woman. The patient presented herself to a medical doctor's office due to a rapidly growing breast tumor. Based on a core needle biopsy, a benign lesion was suspected, and the tumor was surgically resected. On a macroscopic study, the cut surface of the tumor revealed a remarkably cystic and well-circumscribed lesion with an intracystic polypoid component. Microscopically, a variety of findings of epithelial and stromal proliferation were observed. This is an interesting case not only because a fibroadenoma with prominent cystic change is unusual but also because the breast tumor showed a characteristically cystic appearance on its macroscopic view.

[Two Cases of Endobronchial Metastases from Breast Cancer].

Endobronchialmetastasis(EBM)is a rare complication in breast cancer patients. Herein, we report 2 cases of EBM in breast cancer patients. Patient 1 had pulmonary metastases that were treated with hormone therapy and showed long survival after achieving a CR, while patient 2 had multi-organ metastases and died 42 months after the diagnosis of EBM. If bronchial obstruction is observed in a breast cancer patient, early diagnosis of EBM via a bronchoscopic examination is recommended. EBM may not indicate a poor prognosis, and appropriate anti-cancer therapy with palliative intrabronchial therapies can prolong the survival in selected EBM patients.

[Three Cases of Intrathecal Chemotherapy with Ventricular Catheter for the Treatment of Leptomeningeal Metastasis from Breast Cancer].

Leptomeningeal metastasis(LM)is a rare complication in patients with breast cancer. We report 3 cases of LMs in patients with breast cancer who were treated with intrathecal methotrexate via an Ommaya reservoir. In 2 patients, a significant neurological improvement was observed, whereas in 1 patient there was no response. The overall survivals for the patients who experienced improvements were 22 and 9 months. Although we have no evidence for the efficacy of intrathecal chemotherapy for LMs in patients with breast cancer, its effects for some patients could be promising, after reservoir management and drug selection establishment.

[A Case of Skull Base Metastasis of Breast Cancer with Dysphasia, Odynophagia and Dysarthria].

While skull base metastases from breast cancer are not uncommon, there are relatively few reported cases in the literature. We report a case of skull base metastasis of breast cancer that resulted in dysphasia, odynophagia, and dysarthria. The case involved a woman in her 50 s who was diagnosed with cancer of the right breast(cT4N1M0, cStage III B)at another medical institution 9 years previously and who underwent a partial mastectomy and an axillary lymph node dissection following neoadjuvant chemotherapy. She began experiencing neck pain 6 months previously, followed by dysphasia, odynophagia, and dysarthria 1 month previously. The patient was referred to our hospital for detailed examination and treatment. PET-CT and cranial MRI was conducted and detected metastatic lesion from the skull base to the upper cervical vertebrae. An orthopedic surgeon performed a posterior decompression and fusion surgery on the occipital bone, cervical vertebra, and thoracic vertebra. A histological examination of bone tissue extracted during surgery revealed that the breast cancer had metastasized. We then performed irradiation of the cervical vertebra from the cranial base and initiated treatment with zoledronic acid and anastrozole. Symptoms such as dysphasia, odynophagia and dysarthria lessened, and the patient is currently being followedupas an outpatient.

Pathological complete response rate in hormone receptor-negative breast cancer treated with neoadjuvant FEC, followed by weekly paclitaxel administration: A retrospective study and review of the literature.

While tumor size, the presence of inflammatory carcinoma and lymph node involvement are the main prognostic factors of women with locally advanced breast cancer, the prognostic value of the estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2) status has not been fully clarified. The present study examined the therapeutic efficacy of a neoadjuvant fluorouracil, epirubicin and cyclophosphamide regimen (FEC), followed by weekly paclitaxel and/or trastuzumab administration, in the treatment of hormone receptor-negative breast cancer patients. Between April 2012 and February 2014, 14 patients with hormone receptor-negative local breast cancer (triple-negative type, 9 patients; HER2 type, 5 patients) were included in the study. In all cases, the histological type of the primary cancer was invasive ductal carcinoma. Among the 14 women who received the regimen, 5 presented with stage I cancer (35.7%), 3 with stage IIA (21.4%), 3 with stage IIB (21.4%), 1 with stage IIIB (7.1%) and 2 with stage IIIC (14.3%), according to the American Joint Committee on Cancer staging system. With regard to the tumor-node-metastasis classification, 5 patients were T1N0M0 (35.7%), 3 were T2N0M0 (21.4%), 3 were T2N1M0 (21.4%), 2 were T3N3M0 (14.3%) and 1 was T4N1M0 (7.1%). The pathological response was evaluated using resected tissue following neoadjuvant chemotherapy, according to the criteria established by the Japanese Breast Cancer Society. Patients were classified into pathological responders (grades 2 and 3, 71.4% of all patients) and non-responders (grade 1, 28.6% of all patients). A pathological complete response (pCR) was achieved in 50.0% of all cases (7/14); 44.4% of triple-negative-type cases (4/9) and 60.0% of HER2-type cases (3/5). Hematological and non-hematological toxicity was reversible and manageable. No patients withdrew from treatment, and favorable compliance was achieved. The present study demonstrated that neoadjuvant FEC followed by weekly administration of paclitaxel and/or trastuzumab induces a high pathological response and a high pCR rate in patients with hormone receptor-negative breast cancer. Due to the high clinical benefit rate and acceptable safety profile, this regimen should be considered an acceptable neoadjuvant treatment option for hormone receptor-negative breast cancer.

Examination of the clinical efficacy of eribulin and trastuzumab in HER2-positive recurrent breast cancer.

There are limited studies reported that describe the efficacy of eribulin and trastuzumab in the treatment of recurrent breast cancer. The present study examined the therapeutic efficacy of eribulin and trastuzumab in the treatment of recurrent breast cancer. Between October 2011 and August 2013, 5 recurrent breast cancer patients who were treated with eribulin and trastuzumab were included in the study. The cancer stages in the 5 women who received this regimen were stage IIIB in 1 (20%) and stage IV in 4 (80%). The sites of recurrence were the lung in 3 patients, liver in 2, bone in 1, brain in 1, supraclavicular lymph nodes in 1, infraclavicular lymph nodes in 1 and mediastinal lymph nodes in 1. The median number of prior treatment regimens was 5 (range, 5-11). Complete response was achieved in 0 patients, 1 achieved partial response, 3 had stable disease, and 1 had progressive disease. The overall response rate was 20%, and the clinical benefit rate was 80%. Patients also reported grade 3/4 neutropenia (80.0%). However, hematological toxicity was reversible and manageable. The most common grade 3/4 nonhematological toxicities were fatigue (20.0%), peripheral neuropathy (20.0%) and appetite loss (20.0%). No patients withdrew from treatment, and favorable compliance was achieved in the study. The results indicated that eribulin and trastuzumab have the potential to be one of the drugs for treatment of recurrent breast cancer.

Pathological response rate in hormone-positive breast cancer patients treated with neoadjuvant FEC and triweekly docetaxel: a case series.

We recently reported that neoadjuvant 5-FU, epirubicin, and cyclophosphamide (FEC) followed by weekly paclitaxel and/or trastuzumab induced a high pathological complete response (pCR) rate in hormone-negative patients. The present study examined the therapeutic efficacy of neoadjuvant FEC followed by triweekly docetaxel and/or trastuzumab in the treatment of hormone-positive patients. Between February 2012 and December 2013, 16 hormone-positive patients with local breast cancer (luminal A type: six patients; luminal B type: two patients; luminal HER2 type: eight patients) were included in the study. The histological type of the primary cancer was invasive ductal carcinoma in all patients. The cancer stages in the 16 women who received this regimen were stage I in five (31.3%), IIA in four (25.0%), IIB in five (31.3%), IIIB in one (6.3%), and IIIC in one (6.3%). Regarding clinical TNM classification, five patients were T1N0M0, one was T1N1M0, three were T2N0M0, five were T2N1M0, one was T3N2M0, and one was T4N0M0. The pCR was evaluated using resected tissue after neoadjuvant chemotherapy according to the evaluation criteria of the Japanese Breast Cancer Society. Patients were classified into pathologic responders (grade 2: 50.0% of all patients: 2/6 of luminal A type; 6/8 of Luminal HER2 type) and nonresponders (grades 0 and 1: 50.0% of all patients: 4/6 of luminal A type; 2/2 of luminal B type; 2/8 of luminal HER2 type) according to the grade of the tumor. The pCR rate was 0%. Hematologic and nonhematologic toxicity was reversible and manageable. This study demonstrated that neoadjuvant FEC followed by triweekly docetaxel and/or trastuzumab did induce a high pathologic response in luminal HER2 type, but not in luminal A and B types, and did not induce a high pCR rate in the hormone-positive patients.

[A case of Paclitaxel-induced peripheral neuropathy successfully treated with duloxetine].

Here, we report about a 60-year-old woman with metastatic breast cancer who was successfully treated for paclitaxelinduced peripheral neuropathy with duloxetine. She was administered trastuzumab plus paclitaxel(PTX)combination therapy that was ultimately discontinued because of grade 3 peripheral neuropathy detected on day 15, according to the CTCAE (v4.0). She was administered duloxetine on day 90 after the end of the previous therapy because of the peripheral neuropathy. Thereafter, the peripheral neuropathy decreased to grade 1, which enabled PTX administration on her request. Further trials are required to confirm the efficacy of duloxetine.

[Effect of dexamethasone on vascular pain caused by the administration of fosaprepitant dimeglumine and epirubicin hydrochloride in patients with primary breast cancer].

Epirubicin hydrochloride injection is indicated as a therapy for patients with primary breast cancer. This drug has been reclassified as a drug with high emetic potential according to the American Society of Clinical Oncology Guidelines for Antiemetics in Oncology. Therefore, patients who receive this agent should also receive fosaprepitant dimeglumine, an anti-emetic agent. However, it has been reported that fosaprepitant induces vascular pain when used in anthracycline-based regimens administered via the peripheral veins. In order to relieve the fosaprepitant and epirubicin-induced vascular pain associated with vasculitis, dexamethasone was administered at the onset of vascular pain. There is a possibility that the fosaprepitant and epirubicin-induced pain may improve owing to the administration of dexamethasone; however, further trials are required to confirm the effect of this method.

Regioselective synthesis of multisubstituted benzenes by palladium-catalyzed intermolecular reaction of ß-iodo-ß-silylstyrenes with alkynes.

The Pd-catalyzed reaction between ß-iodo-ß-silylstyrenes and terminal alkynes in i-Pr2NEt gave 1,2,3,5-tetrasubstituted benzenes with complete regioselection. The use of certain silylacetylenes as alkynes enabled efficient synthesis of 1,3,5-trissilyl-2-arylbenzenes, which could be transformed into other multisubstituted benzenes by displacement of the silyl groups.

Tumor inhibitory effect of gefitinib (ZD1839, Iressa) and taxane combination therapy in EGFR-overexpressing breast cancer cell lines (MCF7/ADR, MDA-MB-231).

Some kinds of breast cancer cell lines, similar to several types of solid tumors, express epidermal growth factor receptor (EGFR). However, gefitinib, an EGFR tyrosine kinase inhibitor, is not effective for all these cell lines. Similarly, taxane is effective for many of the cell lines, although some, such as the multidrug-resistant MCF7/ADR cell line, show taxane-resistance. Here, we examined the growth inhibitory effect of combination treatment with gefitinib and taxane on the breast cancer cell lines MDA-MB-231 (EGFR-positive) and MCF7/ADR (EGFR- and HER2-positive). To estimate the combined effect, a Combination Index was calculated for each cell line. The combination of gefitinib and taxane showed a strong synergistic effect on MCF7/ADR cells, but an invitro additive-antagonistic effect on MDA-MB-231 cells. Similarly, the combination treatment showed a significantly increased tumor inhibitory effect on MCF7/ADR xenografts, but not on MDA-MB-231 xenografts. Regarding the mechanism of the synergistic effect, Western blotting analysis revealed that taxane activated the EGFR-Akt pathway in MCF7/ADR cells but not in MDA-MB-231. To determine the optimal sequential administration of gefitinib and taxane for MCF7/ADR cells, we used flow cytometry to analyze the cell cycle and apoptosis; finding that taxane treatment followed by gefitinib produced a higher rate of G2 arrest and apoptosis than gefitinib treatment followed by taxane. These results suggest gefitinib overcomes the drug-resistance of these cells, thereby increasing the effects of taxane on MCF7/ADR cells. Further, activation of the EGFR-Akt pathway by taxane is related to this synergistic effect.

Clinical significance of multidetector-row computed tomography in breast surgery.

Several reports support the association of higher ipsilateral breast tumor recurrence rates with positive or intermediate margins compared with negative pathologic margins. Precise evaluation of tumor extension and adequate surgical margin are important factors affecting tumor recurrence after breast-conserving surgery (BCS). Many studies have reported the utility of magnetic resonance imaging (MRI) for diagnosing the tumor extension of breast cancer, but few have evaluated the utility of multidetector-row computed tomography (MDCT). The results of this study show the clinical significance of MDCT for detecting cancer extension and demonstrate the clinical role of MDCT in BCS. Subjects comprised 136 patients grouped into two categories based on whether or not tumor extension was evaluated with MDCT preoperatively. The positive surgical margin rate and breast conservation rate were analyzed in each group and the clinical role of MDCT in BCS was evaluated. Moreover, evaluation of intraductal extension was done both with MDCT and histologically, and computed tomography (CT)-pathologic correlations were examined retrospectively. Finally, the margin-positive cases were analyzed in relation to their clinical characteristics. Sensitivity, specificity, positive predictive value, and negative predictive value for detection of the intraductal component were 71.8%, 85.7%, 82.1%, and 76.9%, respectively. The positive surgical margin rate and conservation rate are 7.46% and 81.9%, respectively, for those who were diagnosed with MDCT preoperatively; their corresponding rates without MDCT were 16.67% and 67.9%. Most margin-positive patients have remarkable lymphatic space invasion. Positive surgical margins were often recognized toward the nipple. For diagnosing the intraductal extension, MDCT shows sufficient diagnosability. Moreover, MDCT can provide appropriate information for the determination of adequate surgical margins and contribute to increases in breast conservation rates.

Proteasome inhibitor bortezomib increases PTEN expression and enhances trastuzumab-induced growth inhibition in trastuzumab-resistant cells.

PTEN (phosphatase and tension homolog deleted on chromosome 10) has been shown to be inactivated in a wide range of cancers and the role of this gene product is associated with the suppression of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway in many cancers. Recently, some reports demonstrated that the degree of PTEN expression could predict trastuzumab chemosensitivity in ErbB2-overexpressing breast cancer. Here, we demonstrate the possible involvement of a proteasome inhibitor (PS341) in PTEN expression and elucidate the influence of PI3K/Akt, one of the main cascades of the ErbB2 downstream pathway, and discuss the role of the proteasome inhibitors in trastuzumab resistance. ErbB2-overexpressing SKBR3 human breast cancer cells and trastuzumab-resistant SKBR3/R cells were analyzed in this study. We show that the expression of phosphorylated Akt was highly increased in trastuzumab-resistant cells, although the expression of PI3K, phosphorylated PI3K and non-phosphorylated Akt was unchanged in comparison with wild-type SKBR3 cells. However, following treatment with PS341, the level of phosphorylated Akt was decreased in a dose-dependent manner. Conversely, the level of PTEN was increased in the same fashion. PS341 showed sufficient cytotoxicity in resistant cells in combination with trastuzumab and the efficacy of trastuzumab was inclined to be better in resistant cells under PS341 treatment. Remarkable activity of Akt was observed in trastuzumab-resistant SKBR3 breast cancer cells and this phenomenon could be associated with the decreased expression of PTEN. The proteasome inhibitor PS341 could increase the level of PTEN and inhibit the downstream pathway of ErbB2, interfering with phosphorylation of Akt.

Gefitinib, an epidermal growth factor receptor blockade agent, shows additional or synergistic effects on the radiosensitivity of esophageal cancer cells in vitro.

Human esophageal cancers have been shown to express high levels of epidermal growth factor receptor (EGFR) and a relationship between high EGFR expression and local advance, the number of lymph node metastases, life expectancy, and sensitivity to chemo-radiotherapy has been demonstrated. We examined the use of gefitinib, an orally active EGFR-selective tyrosine kinase inhibitor, as a new strategy for treatment of esophageal carcinoma. The effects of gefitinib were evaluated in monotherapy and in combination with radiotherapy in human esophageal carcinoma cell lines. Gefitinib produced a dose-dependent inhibition of cellular proliferation in all of the 8 esophageal carcinoma cell lines examined, with IC50 values ranging from 5.7 microM to 36.9 microM. In combination, gefitinib and radiotherapy showed a synergistic effect in 2 human esophageal carcinoma cell lines and an additive effect in 5 cell lines. Western blotting demonstrated that gefitinib blocked activation of the EGFR-extracellular signal-regulated kinase (Erk) pathway and the EGFR-phosphoinositide-3 kinase (PI3K)-Akt pathway after irradiation. These results suggest that further evaluation of EGFR blockade as a treatment for esophageal cancer should be performed, and that radiotherapy combined with EGFR blockade may enhance the response of esophageal carcinoma to therapy.

Multidetector row computed tomography for diagnosing intraductal extension of breast carcinoma.

OBJECTIVES: Several reports supported the association of higher ipsilateral breast tumor recurrence rates with positive or intermediate margins compared with negative pathologic margins. Precise evaluation of intraductal component and adequate surgical margin are important factors affecting the tumor recurrence after breast conserving surgery. Numerous studies have reported the utility of magnetic resonance imaging for diagnosing developing intraductal extension of breast cancer, but few have investigated multidetector-row computed tomography (MD-CT). The present study evaluated the clinical utility of MD-CT for detecting intraductal extension of breast carcinoma, and analyzed clinical parameters affecting the detection of intraductal extension under MD-CT. METHODS: Subjects comprised 44 patients grouped into three categories according to degree of intraductal extension of the main tumor under MD-CT (Intraductal spread grade 1 approximately 3: IDS 1 approximately 3). Tumors were also categorized histopathologically (p-IDS 0 approximately 3), and CT-pathological correlations were examined retrospectively. Clinical parameters were evaluated to determine the affect on detection of intraductal components. RESULTS: MD-CT detected 44 breast lesions (100%). Sensitivity for detection of intraductal component was 81.2%, specificity was 67.8%, and accuracy was 72.7%. Regarding extent of intraductal components, significant correlations were found between histopathological and MD-CT findings. A strong correlation was found in postmenopausal women between T2 tumor and high histological grade. CONCLUSIONS: MD-CT findings of intraductal extension from breast carcinoma correlate with histological degree of intraductal extension, and MD-CT may be useful for preoperative assessment of breast-conserving surgery, particularly for postmenopausal women with histological high nuclear grade and T2 tumor.

Antitumor effect of gefitinib ('Iressa') on esophageal squamous cell carcinoma cell lines in vitro and in vivo.

High expression of epidermal growth factor receptor (EGFR) is thought to be correlated with cell proliferation, invasion, metastasis, resistance to chemoradiotherapy, and poor prognosis in various kinds of human cancers. Blockade of EGFR signal transduction can be a promising strategy for cancer therapy. Approximately 40-70% of esophageal squamous cell carcinomas (ESCCs) show high expression of EGFR. In this study, we examined the antitumor effect of gefitinib, an EGFR tyrosine kinase inhibitor, against ESCC cells in vitro and in vivo. In three ESCC cell lines (TE8, T.T and T.Tn), cell proliferation had been inhibited in a dose-dependent manner and IC(50) values (respectively, 8.49, 18.9 and 17.3muM). Gefitinib inhibited EGF-induced autophosphorylation of EGFR and its downstream signaling pathways, Ras/Raf/MAPK and PI3K/Akt, and caused G(1) arrest of cell cycle and apoptosis confirmed with flow cytometry. We examined the effect of gefitinib on nude mice bearing established TE8 and T.T xenografts. Gefitinib (100 or 200mg/kg once-daily, p.o.) showed antitumor activity in a dose-dependent manner, resulting in a significantly improved survival of treated mice as compared with untreated mice. Immunohistochemical examination of the harvested tumor was performed to examine the status of phosphorylated EGFR, PCNA, Factor VIII and apoptosis. We found inhibition of EGFR phosphorylation, cell cycle arrest (by PCNA staining), decrease of microvessel density (Factor VIII) and induction of apoptosis by TUNEL staining. In conclusion, our findings demonstrate that gefitinib is effective for growth inhibition of ESCC cell lines in vitro and in vivo and suggest that gefitinib may be one of the new therapeutic options for ESSC.

Proteasome inhibitors can alter the signaling pathways and attenuate the P-glycoprotein-mediated multidrug resistance.

Numerous signaling pathways were reported to be involved in the resistance for conventional cytotoxic drugs, although one of the main reasons is the overexpression of P-glycoprotein (P-gp) in multidrug resistant cancer cells. The overexpression of P-gp has been associated with the resistance to a wide range of anticancer drugs. Doxorubicin and paclitaxel are substrates of this transporter system and have an important role for the various human malignancies. In the present study, drug-sensitive MCF7 and multidrug resistant MCF7/ADR (characterized by overexpression of P-gp) human breast cancer cell lines were used as an experimental model. We have found that PS341 and MG132, proteasome inhibitors, reduced the degree of the multidrug resistance (MDR) in MCF7/ADR cells. This phenomenon was accompanied by a decrease in the IC50 value of doxorubicin and paclitaxel from 55.9 +/- 3.46 to 0.60 +/- 0.08 microM, and from 17.61 +/- 1.77 to 0.59 +/- 0.12 microM, respectively. The IC50 values of sensitive cells for doxorubicin and paclitaxel were about 0.42 and 0.83 microM, respectively. The effect of PS341 and MG132 on MCF7/ADR cells was associated with a significant decrease in both protein and gene levels of P-gp expression. Moreover, with regard to the expression of possible signal transduction pathways of mitogen-activated protein kinase (MAPK) related to the activation of mdr1, proteasome inhibitors did significantly influence the activation of these proteins. Western blot analysis revealed that 24 hr exposure of multidrug resistant MCF7/ADR cells with proteasome inhibitors did change the levels of DNA binding activity of nuclear factor-kappaB (NF-kappaB), pERK1/2, c-Jun, and p-c-Jun. In conclusion, we could remark that proteasome inhibitors (especially PS341) attenuate the resistance of MCF7/ADR cells for P-gp substrate drugs of doxorubicin and paclitaxel. Several proteins are supposed to be associated with the resensitization of the cells to conventional cytotoxic drugs, although decreased activity of P-gp is at least involved in the proteasome inhibitor-related resensitization. And influence with MAPK pathways, which have been reported to be associated with the regulation of P-gp, might be contributed to the resensitization brought by proteasome inhibitors.

PLC and PI3K pathways are important in the inhibition of EGF-induced cell migration by gefitinib ('Iressa', ZD1839).

BACKGROUND: Expression of epidermal growth factor receptor (EGFR) by human breast cancer tissues is associated with poor clinical response. The EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib ('Iressa', ZD1839), is a leading example of a molecular targeted agent, and has an anti-proliferative effect on various cancer cells. But the details of the anti-cancer effect and mechanism have not been elucidated. We studied the anti-cancer effect of gefitinib in breast cancer cell lines and the intracellular pathway downstream of EGFR associated with cell migration. METHODS: In this study, we analysed the anti-proliferative and anti-migratory effect of gefitinib in EGFR (+) breast cancer cell lines by WST-1 analysis and chemotaxis chamber analysis. We analyzed several intracellular phosphorylated pathways which are activated by mitogen activated kinases (extracellular signal-regulated protein kinase 1 and 2: MEK), phosphatidylinositol 3'-kinase (PI3K) and phpspholipase C (PLC), by blocking those pathways using inhibitors of each kinase, and also investigated the effects on the phosphorylation of myosin light chain (MLC). RESULTS: Gefitinib inhibited proliferation in most of these cell lines. MDA-MB231 was shown to be resistant. Furthermore, proliferation of MDA-MB231 cells was not affected by EGF stimulation, but migration of MDA-MB231 cells was significantly inhibited. PI3K and PLC inhibitors blocked EGF-stimulated cell migration and MLC phosphorylation, but the MEK inhibitor did not influence cell migration. CONCLUSIONS: Gefitinib has an anti-migratory effect on MDA-MB231 that results in an anti-proliferative effect. PI3K and PLC are important for the migration of MDA-MB231 cells, and gefitinib may inhibit migration by blocking these signalling pathways.