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Progesterone regulates the proliferation of breast cancer cells - in vitro evidence.

Azeez JM, Sithul H, Hariharan I, Sreekumar S, Prabhakar J, Sreeja S, Pillai MR - Drug Des Devel Ther (2015)

Bottom Line: Reports state that surgery performed at different phases of the menstrual cycle may significantly affect breast cancer treatment outcome.Therefore, we further functionally characterized the protein product of TOB-1 in vitro.These results support the hypothesis that surgery conducted during the luteal phase of the menstrual cycle may facilitate improved patient survival.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.

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.

No MeSH data available.


Related in: MedlinePlus

Proposed signaling pathway for TOB-1-mediated progesterone signaling.Notes: TOB-1 was involved in the growth arrest pathway in response to progesterone in MCF-7 cells. The binding of progesterone to progesterone receptor may activate the downstream TOB-1 signaling pathway. At the same time, progesterone can produce ROS, which may result in a change in the antioxidant enzyme balance. Furthermore, it can activate PTEN, which creates an interaction with the tumor suppressor TOB-1 and leads to a change in cell growth properties through its interaction with other tumor-suppressor proteins. The red and green upward arrows indicate upregulation of the specific proteins; the red downward arrows indicate downregulation of the specific proteins.Abbreviations: PG, progesterone; PR, progesterone receptor; ROS, reactive oxygen species; SOD, superoxide dismutase.
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f8-dddt-9-5987: Proposed signaling pathway for TOB-1-mediated progesterone signaling.Notes: TOB-1 was involved in the growth arrest pathway in response to progesterone in MCF-7 cells. The binding of progesterone to progesterone receptor may activate the downstream TOB-1 signaling pathway. At the same time, progesterone can produce ROS, which may result in a change in the antioxidant enzyme balance. Furthermore, it can activate PTEN, which creates an interaction with the tumor suppressor TOB-1 and leads to a change in cell growth properties through its interaction with other tumor-suppressor proteins. The red and green upward arrows indicate upregulation of the specific proteins; the red downward arrows indicate downregulation of the specific proteins.Abbreviations: PG, progesterone; PR, progesterone receptor; ROS, reactive oxygen species; SOD, superoxide dismutase.

Mentions: Surgical intervention is a treatment option for breast cancer patients.35 In 1989, Hrushesky et al6 proposed that the timing of surgical interventions for breast cancer had a substantial influence on the outcome. The option for surgical intervention mainly depends on the cancer stage.36 Subsequently, a number of controversial reports followed.4 Thus, this study attempted to determine a possible molecular explanation for improved patient survival during breast cancer surgery treatment in the luteal phase. Using microarray-based gene expression analyses, we explored several pro-apoptotic and cell cycle-regulating genes in the luteal phase and anti-apoptotic genes in the follicular phase of the menstrual cycle. In clinical practice, the co-expression of PR with ER is currently assessed as a predictive marker for favorable disease prognosis and for response to hormonal therapy. During the secretory phase of the menstrual cycle, when high circulating levels of progesterone are associated with reduced PR expression, PRA was preferentially reduced, resulting in a distinct predominance of PRB.37 The high posttranslational modification of PR dramatically alters its function, receptor localization, and promoter selectivity. Additionally, the function of PR is complex in the context of tissue-specific effects, isoform-specific actions, timing, and hormone delivery dose.38 In the present study, we demonstrated the expression of PRB (Figure 2C) with a moderate concentration of progesterone in vitro, which most likely reflects the expression of PRs at different phases of the menstrual cycle. For the first time, we showed that the protein product of TOB-1 – TOB-1 – which is identified as one of the differentially expressed genes exclusively present in the luteal phase in our tissue microarray study, exerts ROS-regulated antiproliferative activity, followed by modulation of multiple downstream signaling pathways via PR. Jiao et al18 reported that TOB-1 functions as a tumor suppressor by modulating epidermal growth factor receptor and its downstream signaling pathways through a direct or indirect interaction with the key tumor suppressor PTEN. Loss of PTEN expression occurs commonly in breast cancer, which has been associated with loss of ER39 and resistance to cancer therapies.40 Recent reports have shown the regulatory role of PTEN in breast carcinoma cell growth.41 Correlation of PTEN loss with ROS regulation in progesterone-treated cells in vitro has not been well characterized in the literature, with the exception of a few studies that analyzed prognostic parameters. The findings of these studies were consistent with those of our own study and showed a significant reduction in PTEN expression when the TOB-1 function was silenced. Loss of PTEN expression occurs commonly in breast cancer and correlates with disease-related death, lymph node metastasis, and loss of receptor staining.42 Thus, ROS generated due to progesterone promote a survival signal that may ultimately control the function of PTEN. None of the studies compared survival and disease recurrence in connection with PTEN expression. The tumor suppressor protein p53 is a redox-active transcription factor that organizes and directs cellular responses in the face of a variety of stresses, leading to genomic instability. Both ROS and p53 participate in multiple cellular processes, and interactions between, and pathway intersections of ROS and p53 occur.43 Progesterone, which generates ROS in MCF-7 cells, may activate p53 through antioxidant enzyme interactions (Figure 2C). Vurusaner et al43 reported that manganese superoxide dismutase (MnSOD) is suppressed at the promoter level by p53 activation. Suppression of antioxidant genes by p53 is an alternative way to increase cellular ROS, conferring oxidative stress. Reduced MnSOD activity can favor proliferation owing to increased superoxide and low hydrogen peroxide levels, whereas heightened MnSOD activity drives proliferating cells to transition into quiescence owing to increased hydrogen peroxide generation. In this context, the SOD1 and SOD2 balance determines whether a cell proliferates or transitions to a quiescent state. PTEN and PI3K regulate p27 at a posttranscriptional level, and p27 protein stability also increases in cells expressing PTEN.44 Our study revealed that progesterone can activate PTEN, which may further control the activity of p27 at a transcriptional level. As no significant activity or difference in PI3K phosphorylation occurred upon progesterone treatment, PTEN may be active in progesterone signaling through its phosphatase-independent activity. Several studies have demonstrated that PTEN can activate p53 through direct and indirect protein–protein interactions, including phosphatase-dependent and phosphatase-independent mechanisms.41,45 With all of these observations, we propose a model for the action of progesterone in ER/PR-positive breast cancer via PR in a time- and concentration-dependent manner by modulating signaling pathways that include tumor suppressor pathways (Figure 8). Although many questions remain, the current findings may lead to further investigations regarding the impact of menstrual cycle hormones on breast cancer. A better understanding of breast cancer surgery timing could potentially save the lives of women by preventing recurrence of the disease.


Progesterone regulates the proliferation of breast cancer cells - in vitro evidence.

Azeez JM, Sithul H, Hariharan I, Sreekumar S, Prabhakar J, Sreeja S, Pillai MR - Drug Des Devel Ther (2015)

Proposed signaling pathway for TOB-1-mediated progesterone signaling.Notes: TOB-1 was involved in the growth arrest pathway in response to progesterone in MCF-7 cells. The binding of progesterone to progesterone receptor may activate the downstream TOB-1 signaling pathway. At the same time, progesterone can produce ROS, which may result in a change in the antioxidant enzyme balance. Furthermore, it can activate PTEN, which creates an interaction with the tumor suppressor TOB-1 and leads to a change in cell growth properties through its interaction with other tumor-suppressor proteins. The red and green upward arrows indicate upregulation of the specific proteins; the red downward arrows indicate downregulation of the specific proteins.Abbreviations: PG, progesterone; PR, progesterone receptor; ROS, reactive oxygen species; SOD, superoxide dismutase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644174&req=5

f8-dddt-9-5987: Proposed signaling pathway for TOB-1-mediated progesterone signaling.Notes: TOB-1 was involved in the growth arrest pathway in response to progesterone in MCF-7 cells. The binding of progesterone to progesterone receptor may activate the downstream TOB-1 signaling pathway. At the same time, progesterone can produce ROS, which may result in a change in the antioxidant enzyme balance. Furthermore, it can activate PTEN, which creates an interaction with the tumor suppressor TOB-1 and leads to a change in cell growth properties through its interaction with other tumor-suppressor proteins. The red and green upward arrows indicate upregulation of the specific proteins; the red downward arrows indicate downregulation of the specific proteins.Abbreviations: PG, progesterone; PR, progesterone receptor; ROS, reactive oxygen species; SOD, superoxide dismutase.
Mentions: Surgical intervention is a treatment option for breast cancer patients.35 In 1989, Hrushesky et al6 proposed that the timing of surgical interventions for breast cancer had a substantial influence on the outcome. The option for surgical intervention mainly depends on the cancer stage.36 Subsequently, a number of controversial reports followed.4 Thus, this study attempted to determine a possible molecular explanation for improved patient survival during breast cancer surgery treatment in the luteal phase. Using microarray-based gene expression analyses, we explored several pro-apoptotic and cell cycle-regulating genes in the luteal phase and anti-apoptotic genes in the follicular phase of the menstrual cycle. In clinical practice, the co-expression of PR with ER is currently assessed as a predictive marker for favorable disease prognosis and for response to hormonal therapy. During the secretory phase of the menstrual cycle, when high circulating levels of progesterone are associated with reduced PR expression, PRA was preferentially reduced, resulting in a distinct predominance of PRB.37 The high posttranslational modification of PR dramatically alters its function, receptor localization, and promoter selectivity. Additionally, the function of PR is complex in the context of tissue-specific effects, isoform-specific actions, timing, and hormone delivery dose.38 In the present study, we demonstrated the expression of PRB (Figure 2C) with a moderate concentration of progesterone in vitro, which most likely reflects the expression of PRs at different phases of the menstrual cycle. For the first time, we showed that the protein product of TOB-1 – TOB-1 – which is identified as one of the differentially expressed genes exclusively present in the luteal phase in our tissue microarray study, exerts ROS-regulated antiproliferative activity, followed by modulation of multiple downstream signaling pathways via PR. Jiao et al18 reported that TOB-1 functions as a tumor suppressor by modulating epidermal growth factor receptor and its downstream signaling pathways through a direct or indirect interaction with the key tumor suppressor PTEN. Loss of PTEN expression occurs commonly in breast cancer, which has been associated with loss of ER39 and resistance to cancer therapies.40 Recent reports have shown the regulatory role of PTEN in breast carcinoma cell growth.41 Correlation of PTEN loss with ROS regulation in progesterone-treated cells in vitro has not been well characterized in the literature, with the exception of a few studies that analyzed prognostic parameters. The findings of these studies were consistent with those of our own study and showed a significant reduction in PTEN expression when the TOB-1 function was silenced. Loss of PTEN expression occurs commonly in breast cancer and correlates with disease-related death, lymph node metastasis, and loss of receptor staining.42 Thus, ROS generated due to progesterone promote a survival signal that may ultimately control the function of PTEN. None of the studies compared survival and disease recurrence in connection with PTEN expression. The tumor suppressor protein p53 is a redox-active transcription factor that organizes and directs cellular responses in the face of a variety of stresses, leading to genomic instability. Both ROS and p53 participate in multiple cellular processes, and interactions between, and pathway intersections of ROS and p53 occur.43 Progesterone, which generates ROS in MCF-7 cells, may activate p53 through antioxidant enzyme interactions (Figure 2C). Vurusaner et al43 reported that manganese superoxide dismutase (MnSOD) is suppressed at the promoter level by p53 activation. Suppression of antioxidant genes by p53 is an alternative way to increase cellular ROS, conferring oxidative stress. Reduced MnSOD activity can favor proliferation owing to increased superoxide and low hydrogen peroxide levels, whereas heightened MnSOD activity drives proliferating cells to transition into quiescence owing to increased hydrogen peroxide generation. In this context, the SOD1 and SOD2 balance determines whether a cell proliferates or transitions to a quiescent state. PTEN and PI3K regulate p27 at a posttranscriptional level, and p27 protein stability also increases in cells expressing PTEN.44 Our study revealed that progesterone can activate PTEN, which may further control the activity of p27 at a transcriptional level. As no significant activity or difference in PI3K phosphorylation occurred upon progesterone treatment, PTEN may be active in progesterone signaling through its phosphatase-independent activity. Several studies have demonstrated that PTEN can activate p53 through direct and indirect protein–protein interactions, including phosphatase-dependent and phosphatase-independent mechanisms.41,45 With all of these observations, we propose a model for the action of progesterone in ER/PR-positive breast cancer via PR in a time- and concentration-dependent manner by modulating signaling pathways that include tumor suppressor pathways (Figure 8). Although many questions remain, the current findings may lead to further investigations regarding the impact of menstrual cycle hormones on breast cancer. A better understanding of breast cancer surgery timing could potentially save the lives of women by preventing recurrence of the disease.

Bottom Line: Reports state that surgery performed at different phases of the menstrual cycle may significantly affect breast cancer treatment outcome.Therefore, we further functionally characterized the protein product of TOB-1 in vitro.These results support the hypothesis that surgery conducted during the luteal phase of the menstrual cycle may facilitate improved patient survival.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.

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.

No MeSH data available.


Related in: MedlinePlus