PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

Schettini, Francesco; Buono, Giuseppe; Trivedi, Meghana V.; Placido, Sabino De; Arpino, Grazia; Giuliano, Mario

doi:10.1159/000481657

Cited by 19 publications

(18 citation statements)

References 41 publications

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“…PI3K/AKT favors cell proliferation through direct regulation of cell cycle proteins, the cyclins. [23,40]. Our current research, also indicated that after 48h treating by CPT together with the specific PI3K inhibitor-LY294002, the expression levels of cyclin A, cyclin B, cyclin D and CDK2 were further decreased in a dose-dependent manner.…”

Section: Discussionsupporting

confidence: 68%

Inhibition of PI3K/AKT molecular pathway mediated by membrane estrogen receptor GPER accounts for cryptotanshinone induced antiproliferative effect on breast cancer SKBR-3 cells

Shi

Zhao

Cui

et al. 2019

Preprint

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Background : Breast cancer is the most frequently diagnosed cancer among women and the second leading cause of cancer death. Especially nuclear estrogen receptor (nER) negative breast cancer is always with much poor prognosis. In recent years, it was reported that membrane G protein coupled estrogen receptor (GPER), a newly recognized estrogen receptor took essential part in the development and treatment of breast cancer, especially nER negative breast cancer. The present study aimed to investigate the anti nER negative breast cancer effect and its possible molecular pathway of cryptotanshinone (CPT), an important active compound of traditional Chinese medicine Danshen.Methods: The following in vitro tests were performed in nER negative but GPER positive breast cancer SKBR-3 cells. The effect of CPT on cell proliferation rate and cell cycle distribution was evaluated by MTT cell viability test and flow cytometry assay. The role of PI3K/AKT pathway and the mediated function of GPER were tested by western blot and immunofluorescence. Technique of gene silence and the specific GPER agonist G-1 and antagonist G-15 were employed in the experiments to further verify the function of GPER in mediating the anticancer role of CPT. Results: The results showed that proliferation of SKBR-3 cells could be blocked by CPT in a time and dose dependent manner. CPT also exerted antiproliferative activities by arresting cell cycle progression in G1 phase and down regulating the expression level of cyclin A, cyclin B, cyclin D and cyclin-dependent kinase 2 (CDK2). The antiproliferative effect of CPT was further enhanced by G1 and attenuated by G15. Results of western blot and immunofluorescence both showed that PI3K and p-AKT protein expression could be down regulated by CPT and such effects were mediated by GPER which is further demonstrated by GPER gene silence test.Conclusion: Our present study shows that the antiproliferative action of CPT on SKBR-3 cells is realized by inhibition of GPER mediated PI3K/AKT pathway. These findings deserve further validation for serving as useful therapeutic targets.

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Section: Discussionsupporting

confidence: 68%

Inhibition of PI3K/AKT molecular pathway mediated by membrane estrogen receptor GPER accounts for cryptotanshinone induced antiproliferative effect on breast cancer SKBR-3 cells

Shi

Zhao

Cui

et al. 2019

Preprint

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show abstract

“…Consistent with these studies, 48 h treatment with CPT showed an inhibitory effect on the expression of both PI3K and p-AKT. PI3K/ AKT favors cell proliferation through direct regulation of cell cycle protein, the cyclins [25,41]. Our current results, the expression of cyclin A, cyclin B, cyclin D and CDK2 further decreased with the specific PI3K on PI3K expression by using immunofluorescence assay.…”

Section: Discussionsupporting

confidence: 59%

Inhibition of PI3K/AKT molecular pathway mediated by membrane estrogen receptor GPER accounts for cryptotanshinone induced antiproliferative effect on breast cancer SKBR-3 cells

Shi

Zhao

Cui

et al. 2020

BMC Pharmacol Toxicol

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Background: Breast cancer is the most frequently diagnosed malignancy among women and the second leading cause of cancer death worldwide. Among which nuclear estrogen receptor (nER) negative breast cancer is always with much poor prognosis. Recently, membrane G protein coupled estrogen receptor (GPER), a newly recognized estrogen receptor has been documented to take essential part in the development and treatment of breast cancer. The present study was designed to investigate the anti nER negative breast cancer effect of cryptotanshinone (CPT), an important active compound of traditional Chinese medicine Danshen and its possible molecular pathway. Methods: The following in vitro tests were performed in nER negative but GPER positive breast cancer SKBR-3 cells. The effect of CPT on cell proliferation rate and cell cycle distribution was evaluated by MTT cell viability test and flow cytometry assay respectively. The role of PI3K/AKT pathway and the mediated function of GPER were tested by western blot and immunofluorescence. Technique of gene silence and the specific GPER agonist G-1 and antagonist G-15 were employed in the experiments to further verify the function of GPER in mediating the anticancer role of CPT. Results: The results showed that proliferation of SKBR-3 cells could be blocked by CPT in a time and dose dependent manner. CPT could also exert antiproliferative activities by arresting cell cycle progression in G1 phase and down regulating the expression level of cyclin A, cyclin B, cyclin D and cyclin-dependent kinase 2 (CDK2). The antiproliferative effect of CPT was further enhanced by G-1 and attenuated by G-15. Results of western blot and immunofluorescence showed that expression of PI3K and p-AKT could be downregulated by CPT and such effects were mediated by GPER which were further demonstrated by gene silence test. Conclusion: The current study showed that the antiproliferative action of CPT on SKBR-3 cells was realized by inhibition of GPER mediated PI3K/AKT pathway. These findings provide further validation of GPER serving as useful therapeutic target.

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“…Perhaps, the biggest transformation in breast cancer patient management since these trials were performed, however, is the multiplicity of new systemic therapies currently available for patients with recurrent breast cancer, especially for ER-positive and HER2-positive cancers. [33][34][35][36][37][38] Thus, when these old Italian trials were ongoing, tamoxifen was the only form of systemic endocrine therapy available. In the meantime, additional forms of endocrine therapy such as the aromatase inhibitors and the selective estrogen receptor downregulator (SERD), fulvestrant have become available.…”

Section: Traditional Protein Biomarkersmentioning

confidence: 99%

Blood-based biomarkers in breast cancer: From proteins to circulating tumor cells to circulating tumor DNA

2018

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Biomarkers are the key to personalized treatment in patients with breast cancer. While tissue biomarkers are most useful in determining prognosis and upfront predicting response to therapy, circulating protein biomarkers such as CA 15-3 and carcinoembryonic antigen are mainly used in monitoring response to endocrine or chemotherapy in patients with advanced disease. Although several centers measure biomarkers in asymptomatic patients following curative surgery for primary breast cancer, the clinical utility of this practice is unclear. Promising new biomarkers for breast cancer include circulating tumor DNA and circulating tumor cells. In contrast to circulating protein biomarkers, measurement of circulating tumor DNA-based biomarkers is potentially useful in identifying mechanisms of resistance to ongoing therapies as well as identifying new targets for further treatment. To increase clinical utility, both the established and emerging circulating biomarkers should where possible be incorporated into randomized trials evaluating new therapies in patients with breast cancer.

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PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom

Cited by 19 publications

References 41 publications

Inhibition of PI3K/AKT molecular pathway mediated by membrane estrogen receptor GPER accounts for cryptotanshinone induced antiproliferative effect on breast cancer SKBR-3 cells

Inhibition of PI3K/AKT molecular pathway mediated by membrane estrogen receptor GPER accounts for cryptotanshinone induced antiproliferative effect on breast cancer SKBR-3 cells

Inhibition of PI3K/AKT molecular pathway mediated by membrane estrogen receptor GPER accounts for cryptotanshinone induced antiproliferative effect on breast cancer SKBR-3 cells

Blood-based biomarkers in breast cancer: From proteins to circulating tumor cells to circulating tumor DNA

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