Dataset Information

RASSF1A Suppresses Estrogen-Dependent Breast Cancer Cell Growth through Inhibition of the Yes-Associated Protein 1 (YAP1), Inhibition of the Forkhead Box Protein M1 (FOXM1), and Activation of Forkhead Box Transcription Factor 3A (FOXO3A).

ABSTRACT: The estrogen receptor alpha (ER?) is expressed by the majority of breast cancers and plays an important role in breast cancer development and tumor outgrowth. Although ER? is well known to be a specific and efficient therapeutic target, the molecular mechanisms that are responsible for the control of ER? expression and function in the context of breast cancer initiation and progression are complex and not completely elucidated. In previous work, we have demonstrated that the tumor suppressor RASSF1A inhibits ER? expression and function in ER?-positive breast cancer cells through an AKT-dependent mechanism. Transcriptional activators such as forkhead box protein M1 (FOXM1) and forkhead transcription factor 3A (FOXO3A) and signaling pathways such as the Hippo pathway are also known to modulate ER? expression and activity. Here we report that RASSF1A acts as an inhibitor of ER?-driven breast cancer cell growth through a complex, hierarchically organized network that initially involves suppression of the Hippo effector Yes-associated protein 1 (YAP1), which is followed by inhibition of AKT1 activity, increased FOXO3A activity as well as a blockade of FOXM1 and ER? expression. Together our findings provide important new mechanistic insights into how the loss of RASSF1A contributes to ER?+ breast cancer initiation and progression.

SUBMITTER: Roßwag S

PROVIDER: S-EPMC7566002 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

RASSF1A Suppresses Estrogen-Dependent Breast Cancer Cell Growth through Inhibition of the Yes-Associated Protein 1 (YAP1), Inhibition of the Forkhead Box Protein M1 (FOXM1), and Activation of Forkhead Box Transcription Factor 3A (FOXO3A).

Roßwag Sven S Thiede Gitta G Sleeman Jonathan P JP Thaler Sonja S

Cancers 20200921 9

The estrogen receptor alpha (ERα) is expressed by the majority of breast cancers and plays an important role in breast cancer development and tumor outgrowth. Although ERα is well known to be a specific and efficient therapeutic target, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast cancer initiation and progression are complex and not completely elucidated. In previous work, we have demonstrated that the tumor suppressor RAS ...[more]

PMID: 32967092

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Project description:The composition of the prostate microbiome may influence the fate of the cells that may be relevant to prostate morbidity. Several independent studies have reported the presence of the bacterium Propionibacterium acnes in diseased human prostate tissue. It is unclear if the bacterium is an infectious agent, part of a normal prostate microbiota or if it is derived from the skin and accidentally introduced, for instance during a prostate biopsy. Previous research with prostate cell culture and animal models has revealed the capability of P. acnes to establish a low-grade chronic inflammation. However, the fate of primary prostate cells exposed to P. acnes has not been investigated in molecular detail. Here, we investigated the impact of P. acnes on human primary prostate epithelial cells (PrEC). An initial analysis of the host cell response by microarray technology confirmed the inflammation-inducing capability of P. acnes but also showed the deregulation of genes involved in cell cycle, and more specifically in kinetochore and centromere functionality. In particular, we could show and confirm by qPCR that only viable P. acnes downregulated a master regulator of cell cycle progression, FOXM1, as well as its target genes. It was further shown by flow cytometry that P. acnes was indeed able to alter the cell cycle by increasing the number of PrEC cells in S-phase. In search for a molecular explanation we tested the hypothesis that a P.acnes produced berninamycin A-like thiopeptide, that is a structurally closely related to the known FOXM1 inhibitor siomycin A, is responsible for the effect on FOXM1 and the cell cycle. A knock-out mutant in P. acnes was created that lacked the gene encoding the berninamycin A peptide precursor; this mutant was unable to downregulate FOXM1, suggesting that a berninamycin A-like thiopeptide induces cell cycle alterations in PrEC cells. Interestingly, the gene cluster encoding this thiopeptide is restricted to a subtype of P. acnes that is relatively rare on human skin, but more often found in prostate tissue.

Dataset Information

RASSF1A Suppresses Estrogen-Dependent Breast Cancer Cell Growth through Inhibition of the Yes-Associated Protein 1 (YAP1), Inhibition of the Forkhead Box Protein M1 (FOXM1), and Activation of Forkhead Box Transcription Factor 3A (FOXO3A).

Publications

RASSF1A Suppresses Estrogen-Dependent Breast Cancer Cell Growth through Inhibition of the Yes-Associated Protein 1 (YAP1), Inhibition of the Forkhead Box Protein M1 (FOXM1), and Activation of Forkhead Box Transcription Factor 3A (FOXO3A).

Similar Datasets

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