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Anti-cancer action of imidazopyridine BAG1 compounds in steriod hormone receptor-positive breast and prostate cancer

ABSTRACT: Transcriptomics analyses to study the effect of the imidazopyridine X15695 on proliferation of estrogen receptor positive (ER+) breast and androgen receptor positive (AR+) prostate cancer cells. The effect of X15695 was analyzed on vehicle or steroid hormone-treated breast and prostate cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218556 | GEO | 2023/03/13

REPOSITORIES: GEO

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Project description:The cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor’s transcriptional output. Although multiple mechanisms including the tissue-specific coactivators dictate these transcriptional signatures, the feed-forward mechanisms, that evolved to coordinate the cell-type specific transcriptional fulcrums for steroid receptors are not yet identified. In this report, we found that a common feed-forward mechanism between GREB1 and steroid receptors governs the differential effect of GREB1 on steroid hormones in a physiological or pathological context. We found that in physiological (receptive) endometrium, GREB1 is essential for progesterone but not estrogenic responses, whereas in endometriosis, an E2-dependent endometrial pathology, it pre-dominantly mediates estrogenic actions. Specifically, the deletion of GREB1 curtails endometrial receptivity and decidualization, owing to impaired P4-dependent stromal cell proliferation. In contrast, GREB1 is not required for E2-mediated epithelial proliferation of the receptive uterus. Of mechanism, in receptive endometrium, progesterone-induced GREB1 physically interacts with the progesterone receptor on chromatin and functions as a cofactor in a positive feedback mechanism to selectively regulate P4-responses. In pathological conditions (endometriosis), ablation of GREB1 led to the development of smaller endometriotic lesions in mice and reduced E2-driven proliferation of human endometriotic cells. Moreover, E2-induced GREB1 modulated the E2-dependent target gene expression in a feed-forward mechanism. Collectively, acting as a downstream effector, GREB1 governs either P4-responses or E2-responses depending on the physiological or pathological setting. Importantly, this differential action of GREB1 is exerted by a common feed-forward mechanism between GREB1 and steroid receptors, which conceptually advances our understanding of the mechanism(s) that underlie the distinct cell- and tissue-specific actions of steroid hormones.

Project description:Orphan-Nuclear-Receptors (ONRs) are a group of ligand dependent transcriptional factors belonging to the family of Steroid-Nuclear-Receptors, which includes estrogen, progesterone and retinoic acid receptors. The ONR denomination refers to the fact that the endogenous ligands of these 15 nuclear receptors have not yet been identified. The vast majority of ONRs are expressed not only in normal tissues but also in different types of solid tumors, including various types of breast cancer. In the present study, we define the expression levels of the ONR mRNAs in a large panel of 51 cell-lines, which recapitulate the heterogeneity of breast cancer. Ten ONRs are characterized by a relatively high expression level in the majority of the breast cancer cell-lines considered and this is consistent with the high levels of the transcripts observed in mammary tumor tissues. To get insights into the functional role played by the 10 ONRs in the growth/progression of breast cancer, we silenced each receptor with a siRNA approach. Effective silencing of the NR2F2 receptor in 5 different and representative breast cancer cell-lines with two separate siRNAs results in an increased growth of each cell-line consistent with a tumor-suppressive action of the receptor. The effect is independent of the cell phenotype, as it is observed in Estrogen-Receptor and HER2 positive as well as Triple-Negative cell-lines. By converse, silencing of the NR2F6 receptor reduces the growth of the 5 selected cell-lines characterized by high expression levels of the ONR, suggesting an oncogenic action. Once again, the anti-proliferative effects of NR2F6 silencing are evident in all the cell-lines considered and are not associated with any of the 3 breast cancer phenotypes. Stable silencing of NR2F6 following infection of the Estrogen-Receptor positive MCF-7 and the Triple-Negative MDA-MB231 cell-lines with 2 specific and different shRNAs support the oncogenic properties of the ORF. Indeed, these shRNAs reduce the growth and clonogenic ability of the 2 cell-lines. In a first set of studies, we performed whole-genome RNA-sequencing experiments in the shRNA infected MCF-7 cells to get insights into the molecular mechanisms underlying the oncogenic action of NR2F6. Stable silencing of the NR2F6 mRNA and protein results in an up-regulation of the gene-networks involved in the pathways controlling cell-adhesion and cell-cell interactions. As expected, silencing causes down-regulation of the gene-networks involved in cell-cycle and cell-proliferation. In particular, we identify 50 and 9 genes whose expression is up-regulated and down-regulated by the knock-down of the NR2F6 transcription factor. These genes are likely to be direct or indirect targets of NR2F6 transcriptional activity. In a second set of experiments, we identify the endogenous organic molecules capable of interacting with the NR2F6 receptor using a mass-spectrometry based approach. To this purpose, we used NR2F6 immune-precipitates obtained from MCF-7 cells, which we transfected with a full-length NR2F6 cDNA expression plasmid. These studies permitted us to identify palmitoylethanolamide as the only endogenous organic molecule binding NR2F6 with high affinity and reproducibility.

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Anti-cancer action of imidazopyridine BAG1 compounds in steriod hormone receptor-positive breast and prostate cancer

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