Browsing by Author "Loreto Bravo, Maria"

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    Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1
    (BIOSCIENTIFICA LTD, 2012) Diaz, Jorge; Aranda, Evelyn; Henriquez, Soledad; Quezada, Marisol; Espinoza, Estefania; Loreto Bravo, Maria; Oliva, Barbara; Lange, Soledad; Villalon, Manuel; Jones, Marius; Brosens, Jan J.; Kato, Sumie; Cuello, Mauricio A.; Knutson, Todd P.; Lange, Carol A.; Leyton, Lisette; Owen, Gareth I.
    Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mechanisms are still not fully understood. The protease-activated receptors (PARs) are a family of membrane receptors that are activated by serine proteases in the blood coagulation cascade. PAR1 (F2R) has been reported to be involved in cancer cell migration and overexpressed in breast cancer. We herein demonstrate that PAR1 mRNA and protein are upregulated by progesterone treatment of the breast cancer cell lines ZR-75 and T47D. This regulation is dependent on the progesterone receptor (PR) but does not require PR phosphorylation at serine 294 or the PR proline-rich region mPRO. The increase in PAR1 mRNA was transient, being present at 3 h and returning to basal levels at 18 h. The addition of a PAR1-activating peptide (aPAR1) to cells treated with progesterone resulted in an increase in focal adhesion (FA) formation as measured by the cellular levels of phosphorylated FA kinase. The combined but not individual treatment of progesterone and aPAR1 also markedly increased stress fiber formation and the migratory capacity of breast cancer cells. In agreement with in vitro findings, data mining from the Oncomine platform revealed that PAR1 expression was significantly upregulated in PR-positive breast tumors. Our observation that PAR1 expression and signal transduction are modulated by progesterone provides new insight into how the progestin component in hormone therapies increases the risk of breast cancer in postmenopausal women. Journal of Endocrinology (2012) 214, 165-175
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    Progesterone Utilizes Distinct Membrane Pools of Tissue Factor to Increase Coagulation and Invasion and These Effects are Inhibited by TFPI
    (WILEY, 2011) Henriquez, Soledad; Calderon, Claudia; Quezada, Marisol; Oliva, Barbara; Loreto Bravo, Maria; Aranda, Evelyn; Kato, Sumie; Cuello, Mauricio A.; Gutierrez, Jorge; Quest, Andrew F. G.; Owen, Gareth I.
    Tissue factor (TF) serving as the receptor for coagulation factor VII (FVII) initiates the extrinsic coagulation pathway. We previously demonstrated that progesterone increases TF, coagulation and invasion in breast cancer cell lines. Herein, we investigated if tissue factor pathway inhibitor (TFPI) could down-regulate progesterone-increased TF activity in these cells. Classically, TFPI redistributes TF-FVII-FX-TFPI in an inactive quaternary complex to membrane associated lipid raft regions. Herein, we demonstrate that TF increased by progesterone is localized to the heavy membrane fraction, despite progesterone-increased coagulation originating almost exclusively from lipid raft domains, where TF levels are extremely low. The progesterone increase in coagulation is not a rapid effect, but is progesterone receptor (PR) dependent and requires protein synthesis. Although a partial relocalization of TF occurs, TFPI does not require the redistribution to lipid rafts to inhibit coagulation or invasion. Inhibition by TFPI and anti-TF antibodies in lipid raft membrane fractions confirmed the dependence on TF for progesterone-mediated coagulation. Through the use of pathway inhibitors, we further demonstrate that the TF up-regulated by progesterone is not coupled to the progesterone increase in TF-mediated coagulation. However, the progesterone up-regulated TF protein may be involved in progesterone-mediated breast cancer cell invasion, which TFPI also inhibits. J. Cell. Physiol. 226: 3278-3285, 2011. (C) 2011 Wiley Periodicals, Inc.