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      Progesterone regulates the proliferation of breast cancer cells – in vitro evidence

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          Abstract

          Reports state that surgery performed at different phases of the menstrual cycle may significantly affect breast cancer treatment outcome. From previous studies, we identified differentially expressed genes in each menstrual cycle phase by microarray, then subjected them to functional in vitro analyses. Microarray studies disclosed genes that are upregulated in the luteal phase and follicular phase. TOB-1 is a tumor suppressor gene and was expressed exclusively in the luteal phase in our microarray study. Therefore, we further functionally characterized the protein product of TOB-1 in vitro. To our knowledge, no studies have yet been conducted on reactive oxygen species-regulated tumor suppressor interactions in accordance with the biphasic nature of progesterone. This work demonstrates that progesterone can produce reactive oxygen species in MCF-7 cells and that TOB-1 exerts a series of non-genomic interactions that regulate antiproliferative activity by modulating the antioxidant enzyme superoxide dismutase. Furthermore, this study implicates PTEN as an interacting partner for TOB-1, which may regulate the downstream expression of cell cycle control protein p27 via multiple downstream signaling pathways of progesterone through a progesterone receptor, purely in a time- and concentration-dependent manner. These results support the hypothesis that surgery conducted during the luteal phase of the menstrual cycle may facilitate improved patient survival.

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          Most cited references 41

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          PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms.

          We show in this study that PTEN regulates p53 protein levels and transcriptional activity through both phosphatase-dependent and -independent mechanisms. The onset of tumor development in p53(+/-);Pten(+/-) mice is similar to p53(-/-) animals, and p53 protein levels are dramatically reduced in Pten(-/-) cells and tissues. Reintroducing wild-type or phosphatase-dead PTEN mutants leads to a significant increase in p53 stability. PTEN also physically associates with endogenous p53. Finally, PTEN regulates the transcriptional activity of p53 by modulating its DNA binding activity. This study provides a novel mechanism by which the loss of PTEN can functionally control "two" hits in the course of tumor development by concurrently modulating p53 activity.
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            Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis.

            PTEN (also known as MMAC-1 or TEP-1) is one of the most frequently mutated tumor suppressors in human cancer. It is also essential for embryonic development. PTEN functions primarily as a lipid phosphatase to regulate crucial signal transduction pathways; a key target is phosphatidylinositol 3,4,5-trisphosphate. In addition, it displays weak tyrosine phosphatase activity, which may downmodulate signaling pathways that involve focal adhesion kinase (FAK) or Shc. Levels of PTEN are regulated in embryos and adult organisms, and gene-targeting studies demonstrate that it has a crucial role in normal development. Functions for PTEN have been identified in the regulation of many normal cell processes, including growth, adhesion, migration, invasion and apoptosis. PTEN appears to play particularly important roles in regulating anoikis (apoptosis of cells after loss of contact with extracellular matrix) and cell migration. Gene targeting and transient expression studies have provided insight into the specific signaling pathways that regulate these processes. Characterization of the diverse signaling networks modulated by PTEN, as well as the regulation of PTEN concentration, enzymatic activity, and coordination with other phosphatases, should provide intriguing new insight into the biology of normal and malignant cells.
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              Tumor suppressor genes and ROS: complex networks of interactions.

              Tumor suppressor genes regulate diverse cellular activities including DNA damage repair, cell cycle arrest, mitogenic signaling, cell differentiation, migration, and programmed cell death. In this review the tumor suppressor genes p53, FoxO, retinoblastoma (RB), p21, p16, and breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) and their roles in oxidative stress are summarized with a focus on the links and interplay between their pathways and reactive oxygen species (ROS). The results of a number of studies have demonstrated an antioxidant role for tumor suppressor proteins, activating the expression of some well-known antioxidant genes in response to oxidative stress. On the other hand, recent studies have revealed a pro-oxidant role for p53 by which cellular ROS are increased by enhanced transcription of proapoptotic genes. A tightly regulated feedback loop between ROS and FoxO proteins, with ROS regulating FoxO activity through posttranslational modifications and protein interactions and FoxO controlling intracellular ROS levels, has been demonstrated. Furthermore, these studies have shown that FoxO transcription factors and p38 mitogen-activated protein kinases may interact with the RB pathway under stress conditions. In addition, cellular senescence studies established an unexpected role for ROS in inducing and maintaining senescence-induced tumor suppression that blocks cytokinesis to ensure senescent cells never divide again. p21 and p16 have been shown to act as tumor suppressor proteins and this function extends beyond cell cycle control and includes important roles in regulating oxidative stress. Consequently, these important interactions indicate a critical potential role for tumor suppressor genes in the cellular response against oxidative stress and emphasize links between ROS and tumor suppressor genes that might be therapeutic targets in oxidative damage-associated diseases. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                09 November 2015
                : 9
                : 5987-5999
                Affiliations
                [1 ]Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
                [2 ]Division of Surgical Oncology, Regional Cancer Centre, Thiruvananthapuram, India
                Author notes
                Correspondence: Sreeharshan Sreeja, Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud Post Office, Thiruvananthapuram, Kerala 695 014, India, Tel +91 471 252 9474, Fax +91 471 234 8096, Email ssreeja@ 123456rgcb.res.in
                Article
                dddt-9-5987
                10.2147/DDDT.S89390
                4644174
                © 2015 Azeez et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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