cyclin-d1 and butylbenzyl-phthalate

Breast cancer is the most common cancer among women worldwide. Butyl benzyl phthalate (BBP) is ubiquitous in human's environment, and is strongly linked to breast cancer development. microRNA (miRNA) is an important regulator of target genes. So far, no studies have been reported yet to reveal the action of miRNAs in BBP-mediated breast cancer cell proliferation. In this study, we showed that BBP induced proliferation of both ER(+) MCF-7 and ER(-) MDA-MB-231 breast cancer cells, proved by increased cell viability, transition of cell cycle from G1 to S phase, upregulation of proliferating cell nuclear antigen (PCNA) and Cyclin D1, and downregulation of p21. Meanwhile, the expression of oncogenic miR-19a/b and PTEN/AKT/p21 axis was also modulated by BBP. Furthermore, for the first time we revealed that miR-19 played crucial role in the promoting effect of BBP on breast cancer cells through targeting PTEN 3'UTR. Findings from this study could provide an important new perspective on the molecular mechanisms through which BBP exerts its promoting effect on breast cancer as well as its target intervention.

Topics: 3' Untranslated Regions; Binding Sites; Breast Neoplasms; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Female; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; MicroRNAs; Phthalic Acids; Plasticizers; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptors, Estrogen; Signal Transduction; Time Factors

Prostate cancer is one of the most commonly diagnosed cancers in man. Studies have shown that phthalates may act as promoters in various types of cancer; however, the role of phthalates in prostate cancer has been rarely reported. The MAPK/AP-1 pathway is a vital regulator of cell proliferation in cancer. In this report we found that three typical phthalates, diethylhexyl phthalate (DEHP), Butyl benzyl phthalate (BBP) and Dibutyl phthalate (DBP), up-regulated cyclinD1 and PCNA, down-regulated P21, inducing proliferation of prostate cancer cells. Furthermore, we found that phthalates increased the expression of p-ERK5 and p-p38, along with upregulation of AP-1 (p-c-fos and p-c-jun). In studies with ERK5 and a p38 inhibitor, our data showed that downregulation of p-ERK5 or p38 inhibited phthalate-triggered cell proliferation. Taken together, findings from this study suggest that phthalates activate MAPK/AP-1 pathway and may potentially promote cell proliferation in prostate cancer, thus providing new insight into the effects and the underlying mechanism of phthalates on prostate cancer.

Topics: Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Dibutyl Phthalate; Diethylhexyl Phthalate; Gene Expression Regulation, Neoplastic; Humans; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 7; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Phthalic Acids; Proliferating Cell Nuclear Antigen; Prostatic Neoplasms