Yehui Shi

Poorer Survival of Male Breast Cancer Compared with Female Breast Cancer Patients May Be Due to Biological Differences

OBJECTIVE The objective of the study was to compare disease-free survival and overall survival in a group of matched males and females with breast cancer, and to analyze possible treatment- and gender-related differences. METHODS We retrospectively analyzed the data of 150 operable male breast cancer patients treated in our hospital from December 1980 to June 2012. Each male breast cancer patient recorded in the database was matched with two female breast cancer patients of equal stage. Prognosis in terms of disease-free survival and overall survival was evaluated. RESULTS The mean age at diagnosis was 58.6 ± 9.7 years for males and 57.2 ± 10.3 years for females. The median follow-up was 69 months for males and 81 months for females. Significant differences were identified for tumor location, hormone receptor status, molecular subtypes and hormone therapy between the two groups. Monofactorial analysis demonstrated that tumor size, lymph node state, American Joint Committee on Cancer stage, molecular subtypes and adjuvant chemotherapy treatment were prognostic factors in male breast cancer patients. The 5- and 10-year disease-free survival rates were 65.6 and 40.1% for males, and 74.9 and 51.5% for females, respectively. The 5- and 10-year overall survival rates were 72.9 and 53.9% for males, and 83.2 and 68.5% for females, respectively. There was significantly difference in disease-free survival and overall survival between the two matched groups (P = 0.002). CONCLUSIONS Male breast cancer patients had inferior outcome despite of equal stage in comparison with matched female breast cancer patients, which demonstrates that biological differences may contribute to the worse prognosis.

Micheliolide overcomes KLF4-mediated cisplatin resistance in breast cancer cells by downregulating glutathione.

Micheliolide (MCL) is a promising novel compound with broad-spectrum anticancer activity. However, little is known regarding its action and mechanism in breast cancer. To explore the potential therapeutic application of MCL as a chemosensitivity modulator, this study investigated the effects of MCL on cisplatin sensitivity in breast cancer and the underlying mechanisms. In the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity assay and a xenograft tumor model, MCL enhanced the cisplatin sensitivity of the breast cancer cell line MCF-7 both in vitro and in vivo. Treatment of MCF-7 cells with low-dose cisplatin (10 µM) was sufficient to enrich the proportion of ALDH+ cells and upregulate Krüppel-like factor 4 (KLF4) expression. The results obtained from knockdown and overexpression experiments demonstrate that KLF4 is both necessary and sufficient to induce a cisplatin resistance phenotype in breast cancer cells. Furthermore, the glutathione (GSH) content was elevated in MCF-7 cells after overexpression of KLF4. KLF4-mediated resistance to cisplatin was found to be abrogated by treatment with buthionine sulfoximine, an inhibitor of GSH synthesis. MCL induced GSH depletion and severe cell death in KLF4-overexpressing MCF-7 cells following exposure to cisplatin. Therefore, these results suggest that MCL-mediated direct depletion of GSH represents a major mechanism in reversing KLF4-induced cisplatin resistance in MCF-7 cells.

Dynamin-related protein 1 is involved in micheliolide-induced breast cancer cell death

Dynamin-related protein 1 (Drp1) is a newly discovered therapeutic target for tumor initiation, migration, proliferation, and chemosensitivity. Thus, therapeutic strategies that focus on targeting Drp1 and its related signaling pathway pave a new way to address the ineffectiveness of traditional cancer therapies. Micheliolide (MCL), a guaianolide sesquiterpene lactone, can selectively eradicate acute myeloid leukemia stem or progenitor cells. But the effect of MCL on the mitochondrial dynamics of cancer cells is still not well demonstrated. In this study, we show that MCL inhibited the growth of MCF-7 human breast cancer cells, accompanied by increased mitochondrial fission and upregulation of Drp1. The results obtained from overexpression experiments of wild or dominant-negative mutant type of Drp1 demonstrate that Drp1 is both necessary and sufficient to induce MDA-MB-231 and MCF-7 cell death. Furthermore, mitochondrial membrane potential decreased, whereas reactive oxygen species (ROS) generation, cytochrome c release, and PARP cleavage were enhanced after overexpression of Drp1 wild type. On the other hand, overexpression of Drp1-K38A (a dominant-negative mutant of Drp1) rescued cells from increased apoptosis, confirming the role of MCL-induced Drp1 in the observed apoptosis. Finally, MCL-induced Drp1-mediated cell death could be reversed by N-acetyl-L-cysteine (the ROS scavenger) in breast cancer cells. Taken together, the present study shows a novel role for Drp1 in MCL-induced breast cancer cell death, potentially through regulation of ROS–mitochondrial apoptotic pathway.

Benefit of everolimus as a monotherapy for a refractory breast cancer patient bearing multiple genetic mutations in the PI3K/AKT/mTOR signaling pathway

A postmenopausal patient with a diagnosis of estrogen receptor (ER) (+), progesterone receptor (PR) (+), and human epidermal growth factor receptor-2 (HER2) (-) breast cancer was reported. The patient refused surgery and was resistant to conventional chemotherapy regimens. Computed tomography and the circulating tumor cell test indicated that the patient’s tumor burden increased rapidly even after several chemotherapy sessions. Multiple genetic aberrances in the phosphatidylinositol3-kinases (PI3K) signaling pathway were detected via next-generation sequencing (NGS)-based liquid biopsy, including a p. G1007R missense mutation in exon 21 of PIK3CA (33.61%), a p.L70fs frameshift mutation in exon 3 of phosphatase and tension homolog deleted on chromosome ten (PTEN) (49.14%), and a p. D1542Y missense mutation in exon 32 of mammalian target of rapamycin (mTOR) (1.66%). Therefore, only the mTOR inhibitor everolimus was administered to the patient. Partial remission (PR) was observed after 2 months, and sustained stable disease (SD) was observed after a year and a half. Subsequent sequencing showed that the mutation ratio of PIK3CA decreased to 4.17%, and that the PTEN and mTOR mutations disappeared, which revealed the significant curative effect of everolimus. We report the first case of successful monotherapy treatment using everolimus in a patient with advanced breast cancer bearing mutations in genes involved in the PI3K/ARK/mTOR signaling pathway. The success of this case highlights the invaluable clinical contribution of NGS-based liquid biopsy, as it successfully provided an optimal therapeutic target for the patient with advanced breast cancer.