Transcriptional responses to direct and indirect TGFβ1 stimulation in cancerous and noncancerous mammary epithelial cells.

Author:

Janus Patryk1ORCID,Kuś Paweł2ORCID,Jaksik Roman2ORCID,Vydra Natalia1ORCID,Toma-Jonik Agnieszka1ORCID,Gramatyka Michalina1ORCID,Kurpas Monika2ORCID,Kimmel Marek3ORCID,Widłak Wiesława1ORCID

Affiliation:

1. Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch

2. Department of Systems Biology and Engineering, Silesian University of Technology

3. Departments of Statistics and Bioengineering, Rice University

Abstract

Abstract Background: Transforming growth factor-beta (TGFβ) is important for the morphogenesis and secretory function of the mammary gland. It is one of the main activators of the epithelial–mesenchymal transition (EMT), a process important for tissue remodeling and regeneration, but also providing cells with the plasticity to form metastases during tumor progression. Noncancerous and cancer cells respond differently to TGFβ. However, knowledge of the cellular signaling cascades triggered by TGFβ in various cell types is still limited. Methods: MCF10A (noncancerous, originating from fibrotic breast tissue) and MCF7 (cancer, estrogen receptor-positive) breast epithelial cells were treated with TGFβ1 directly or through conditioned media from stimulated cells. Transcriptional changes (via RNA-seq) were assessed in untreated cells and after 1-6 days of treatment. Differentially expressed genes were detected with DESeq2 and the hallmark collection was selected for gene set enrichment analysis. Results: TGFβ1 induces EMT in both the MCF10A and MCF7 cell lines but via slightly different mechanisms (signaling through SMAD3 is more active in MCF7 cells), and many EMT-related genes are expressed in MCF10A cells at baseline. Both cell lines respond to TGFβ1 by decreasing the expression of genes involved in cell proliferation: through the repression of MYC (and its targets) in MCF10A cells and the activation of p63-dependent signaling in MCF7 cells (CDKN1A and CDKN2B, which are responsible for the inhibition of cyclin-dependent kinases, are upregulated). In addition, estrogen receptor signaling is inhibited and caspase-dependent cell death is induced only in MCF7 cells. Moreover, direct incubation with TGFβ1 and treatment of cells with conditioned media similarly affected transcriptional profiles. However, TGFβ1-induced protein secretion is more pronounced in MCF10A cells; therefore, the signaling is propagated through conditioned media (bystander effect) more effectively in MCF10A cells than in MCF7 cells. Conclusions: Estrogen receptor-positive breast cancer patients may benefit from high levels of TGFB1 expression due to the repression of estrogen receptor signaling, inhibition of proliferation, and induction of apoptosis in cancer cells. However, some TGFβ1-stimulated cells may undergo EMT, which increases the risk of metastasis.

Funder

Narodowe Centrum Nauki

European Social Fund

Publisher

Research Square Platform LLC

Reference81 articles.

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3