Elucidating progesterone effects in breast cancer: Cross talk with PDGF signaling pathway in smooth muscle cell

Abstract

Several studies indicate that progesterone exerts relevant effects in breast tissue. However, the exact role of this steroid in breast cancer development and progression has not been elucidated. Here, we show that platelet-derived growth factor (PDGF)-A is one of the progesterone target genes on breast cancer MCF7 and T47D cells. A paracrine role for PDGF-A was investigated, since its receptor expression was down-regulated from breast cancer cells. Progesterone increased PDGF-A protein release as evaluated by Western blotting and ELISA. Medium from Progesterone-treated MCF7 cells resulted in phosphorylation of smooth muscle cells PDGF receptor a. This effect was not observed after treatment with PDGF inhibitor. MCF7 cells-secreted PDGF-A was able to increase smooth muscle cell viability and proliferation and decrease apoptosis, effects that were prevented by the use of a PDGF-A neutralizing antibody. Notably, cell invasion was not influenced by PDGF-A secreted by MCF7 cells. Our results elucidated for the first time the cross talk between progesterone and PDGF signaling pathway. The fact that MCF7-secreted PDGF elicited crucial roles in vascular wall smooth muscle cells, suggested a paracrine pathway for progesterone. Targeting these progesterone-induced processes may provide novel therapeutic strategies for hormone-dependent human breast cancer.

Progesterone sensitizes breast cancer MCF7 cells to imatinib inhibitory effects

“…Cells were grown at 378C in a humidified 5% CO 2 atmosphere. In agreement with previous studies, incubations with the distinct agents were performed for 24 h in serum-free conditions [Soares et al, 2007].…”

“…P4 was dissolved in 100% ethanol and added to serum-free medium of cell cultures at a final concentration of 10 À8 M. Concentration for P4 was chosen from a set of five different concentrations ranging from 0.1 to 1,000 nM in previous studies [Soares et al, 2007]. Ethanol was added to cell culture media at a concentration of 0,01% (v/v).…”

“…Because P4 receptor (PR) is an estrogendependent gene product, cells were maintained in 10% FBS and 1% penicillin/streptomycin until 70% confluence, then washed twice with PBS and immediately incubated in serum-free conditions, with no prior serum-free medium incubation, as previously described [Soares et al, 2007].…”

“…Breast cancer continues to be the most common cancer and the second leading cause of cancer death and morbidity among women in the western world [Soares et al, 2007]. Therefore, the constant search for new therapeutic targets which may result in better disease-free and overall survival becomes of primary relevance [Carvalho et al, 2005;Gonzales-Angulo et al, 2006].…”

“…Previous studies of our group showed that incubation of hormone-dependent breast cancer MCF7 cells with progesterone (P4) results in the expression of several genes, namely those involved in platelet-derived growth factor (PDGF) signaling pathway [Soares et al, 2007]. PDGF receptors (PDGFRs) a e b are characterized by an intracellular tyrosine kinase domain and its action depends on ligand binding [George, 2001;Alvarez et al, 2006].…”