Progesterone Induces ERK 1/2 Activation and AP-1 DNA Binding Activity through a Mechanisms Involving Src Kinase and EGFR Transactivation in MCF-7 Breast Cancer Cell.
Fernando Candanedo Gonzalez, Pedro Cotes Reynosa, Adriana Soto Guzman, Margarita Guaderrama, Teresa Robledo, Eduardo Perez Salazar. CINVESTAV-IPN, Mexico City, DF, Mexico
Background: In Mexico, breast cancer is the second most frequent malignancy and occurs in 46% of cases of women younger than 50 years of age. About 75% of breast tumors are positive for the progesterone receptor (PgR) which is expressed in several breast cancer cell lines and its stimulation with progesterone induces cell proliferation. However, the signal transduction pathways activated by progesterone have not been studied in detail. The activating protein-1 (AP-1) transcription factor transduces growth signals through signal transduction pathways to the nucleus, leading to the expression of genes involved in growth and malignant transformation in many cell types. In order to elucidate the signaling pathways whereby progesterone modulate cell proliferation, we investigated the effects of progesterone administration on AP-1 expression. We hypothesized that PgR induced activation of AP-1 transcription factor to induced the growth of breast cancer cells.
Design: To determine whether PgR modulates the AP-1 DNA binding, MCF7 breast cancer cells were treated with progesterone (100 nM) for 30 min and evaluated by electrophoretic mobility shift assay, Wstern blot and proliferative assays.
Results: Our results demosntrate that stimulation of MCF-7 cells with progesterone hormone promote the rapidly phosphorylation of ERK 1/2 at Thr-202 and Tyr-204 and the formation of AP-1-DNA complex in a fashion dependent of Src kinase activity and EGFR transactivation. Furthermore, proliferation induced by progesterone is restricted to breast cancer cells in a fashion dependent of ER1/2 and AP-1 activation.
Conclusions: These results suggest that some the progesterone effects in breast cells are mediated through induction of AP-1 complex expression and consequently through modulation of the AP-1 dependent gene expression. Our data indicate that proliferation induced by progesterone is restricted to breast cancer cells, and that ERK1/2 activation and AP-1-DNA complex formation are mediated by Src family kinases and transactivation of EGFR.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 229, Wednesday Morning