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Mutual editing of alternative splicing between breast cancer cells and macrophages.

ABSTRACT: Breast cancer is a highly heterogeneous disease and numerous secreted factors may differentially contribute to a macrophage phenotype whose extensive infiltration is generally regarded as indicative of an unfavorable outcome. How different breast tumor cells and macrophage cells interplay or influence each other on the alternative splicing (AS) level have not been characterized. Here, we exploited one previous study, which investigated the interplay between macrophages and estrogen receptor?positive (ER+) breast cancer and triple?negative breast cancer (TNBC) at the transcriptional level, to investigate the tumor?macrophage crosstalk at the AS level. In the present study, it was demonstrated that biological processes such as DNA damage and DNA repair were significantly affected both in ER+ breast cancer and TNBC by co?culturing with macrophages, whereas biological pathways altered in macrophages co?cultured with tumor cells depended on the breast cancer type. Specifically, biological processes altered in macrophages co?cultured with ER+ breast cancer were enriched in RNA processing and translation?related pathways whereas biological processes altered in macrophages co?cultured with TNBC were mainly enriched in protein transport pathways. We also analyzed the sequence features of skip exons among different conditions. In addition, putative splicing factors which were responsible for the altered AS profile in each condition were identified. The findings of the present study revealed significant tumor?macrophage crosstalk at the AS level which may facilitate the development of new therapeutic strategies for cancer.

SUBMITTER: Ding W

PROVIDER: S-EPMC6609318 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Mutual editing of alternative splicing between breast cancer cells and macrophages.

Ding Wanbao W Li Dongdong D Zhang Peixian P Shi Lan L Dai Hui H Li Yan Y Bao Xin X Wang Yue Y Zhang Honglei H Deng Lei L

Oncology reports 20190618 2

Breast cancer is a highly heterogeneous disease and numerous secreted factors may differentially contribute to a macrophage phenotype whose extensive infiltration is generally regarded as indicative of an unfavorable outcome. How different breast tumor cells and macrophage cells interplay or influence each other on the alternative splicing (AS) level have not been characterized. Here, we exploited one previous study, which investigated the interplay between macrophages and estrogen receptor‑posi ...[more]

PMID: 31233192

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Project description:BackgroundEstrogens play an important role in breast cancer (BC) development and progression; when the two isoforms of the estrogen receptor (ERα and ERβ) are co-expressed each of them mediate specific effects of these hormones in BC cells. ERβ has been suggested to exert an antagonist role toward the oncogenic activities of ERα, and for this reason it is considered an oncosuppressor. As clinical evidence regarding a prognostic role for this receptor subtype in hormone-responsive BC is still limited and conflicting, more knowledge is required on the biological functions of ERβ in cancer cells. We have previously described the ERβ and ERα interactomes from BC cells, identifying specific and distinct patterns of protein interactions for the two receptors. In particular, we identified factors involved in mRNA splicing and maturation as important components of both ERα and ERβ pathways. Guided by these findings, here we performed RNA sequencing to investigate in depth the differences in the early transcriptional events and RNA splicing patterns induced by estradiol in cells expressing ERα alone or ERα and ERβ.ResultsExon skipping was the most abundant splicing event in the post-transcriptional regulation by estradiol. We identified several splicing events induced by ERα alone and by ERα+ERβ, demonstrating for the first time that ERβ significantly affects estrogen-induced splicing in BC cells, as revealed by modification of a subset of ERα-dependent splicing by ERβ, as well as by the presence of splicing isoforms only in ERβ+cells. In particular, we observed that ERβ+BC cell lines exhibited around 2-fold more splicing events than the ERβ- cells. Interestingly, we identified putative direct targets of ERβ-mediated alternative splicing by correlating the genomic locations of ERβ and ERα binding sites with estradiol-induced differential splicing in the corresponding genes.ConclusionsTaken together, these results demonstrate that ERβ significantly affects estrogen-induced early transcription and mRNA splicing in hormone-responsive BC cells, providing novel information on the biological role of ERβ in these tumors.

Dataset Information

Mutual editing of alternative splicing between breast cancer cells and macrophages.

Publications

Mutual editing of alternative splicing between breast cancer cells and macrophages.

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