AUTHOR=Amer Hoda T. , Eissa Reda A. , El Tayebi Hend M. 

TITLE=A cutting-edge immunomodulatory interlinkage between HOTAIR and MALAT1 in tumor-associated macrophages in breast cancer: A personalized immunotherapeutic approach

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.1032517

DOI=10.3389/fmolb.2022.1032517

ISSN=2296-889X

ABSTRACT=Breast cancer (BC) is one of the most common cancers accounting for 2.3 million cases worldwide. BC can be subclassified molecularly into: Luminal A, Luminal B HER2- ,  Luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These molecular subtypes differ in their prognosis and treatment strategies, thus understanding the tumor microenvironment (TME) of BC could lead to new potential treatment strategies. TME hosts populations of cells that act as anti-tumorigenic such as Tumor-associated eosinophils or Pro-tumorigenic such as Cancer-associated fibroblasts (CAFs), Tumor-associated neutrophils (TANs), Monocytic derived populations such as MDSCs or most importantly “Tumor-associated Macrophages (TAMs)” which are derived from the CD14+ Monocytes. TAMs are reported to have the pro-inflammatory phenotype M1 which is found only in the very early stages of a tumor and is not correlated with progression, however, M2 phenotype is anti-inflammatory that is correlated with tumor progression and metastasis. The current study focused on controlling the anti-inflammatory activity in TAMs of hormonal, HER2+, and TNBC by epigenetic fine-tuning of two immunomodulatory proteins namely CD80 and Mesothelin (MSLN) which are known to be overexpressed in BC with pro-tumorigenic activity. Long non-coding RNAs are crucial key players in tumor progression whether by acting as oncogenic or tumor suppressors. We focused on the regulatory role of MALAT-1 and HOTAIR lncRNAs and their role in controlling the tumorigenic activity of TAMs. This study observed the impact of manipulation of MALAT-1 and HOTAIR on the expression of both CD80 and MSLN in TAMs of BC. Moreover, we analysed the interlinkage between HOTAIR and MALAT-1 as regulators to one another in TAMs of BC. The current study reported an upstream regulatory effect of HOTAIR on MALAT-1. Moreover, our results showed a promising use of MALAT-1 and HOTAIR in regulating oncogenic immune-modulatory proteins MSLN and CD80 in TAMs of HER2+ and TNBC. The downregulation of MALAT-1 and HOTAIR resulted in the upregulation of CD80 and MSLN which indicates that they might have a cell-specific activity in TAMs. These data shed the light on novel key players affecting the anti-inflammatory activity of TAMs as a possible therapeutic target in HER2+ and TNBC.