Citation: Bach, V.N.; Ding, J.; Yeung, M.; Conrad, T.; Odeh, H.N.; Cubberly, P.; Figy, C.; Ding, H.-F.; Trumbly, R.; Yeung, K.C. A Negative Regulatory Role for RKIP in Breast Cancer Immune Response. Cancers 2022, 14, 3605. https://doi.org/10.3390/ cancers14153605 Academic Editor: Constantin N. Baxevanis Received: 30 June 2022 Accepted: 19 July 2022 Published: 24 July 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Article A Negative Regulatory Role for RKIP in Breast Cancer Immune Response Vu N. Bach 1 , Jane Ding 2 , Miranda Yeung 1 , Taylor Conrad 1 , Hussain N. Odeh 1 , Paige Cubberly 1 , Christopher Figy 1 , Han-Fei Ding 2 , Robert Trumbly 1,3, * ,† and Kam C. Yeung 1, * ,† 1 Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Health Science Campus, Toledo, OH 43614, USA; vbach@rockets.utoledo.edu (V.N.B.); miranda.yeung@utoledo.edu (M.Y.); taylor.conrad@utoledo.edu (T.C.); hussain.odeh@rockets.utoledo.edu (H.N.O.); paige.cubberly@rockets.utoledo.edu (P.C.); christopher.figy@rockets.utoledo.edu (C.F.) 2 Georgia Cancer Center, Medical College of Georgia, Augusta University, Georgia, GA 30912, USA; jding@augusta.edu (J.D.); hding@augusta.edu (H.-F.D.) 3 Department of Medical Education, College of Medicine and Life Sciences, University of Toledo, Health Science Campus, Toledo, OH 43614, USA * Correspondence: robert.trumbly@utoledo.edu (R.T.); kam.yeung@utoledo.edu (K.C.Y.) † These authors contributed equally to this work. Simple Summary: Breast cancer is the second most common cancer in women worldwide. Regulation of breast cancer metastasis remains an elusive phenomenon. Elucidating the mechanistic pathway of metastatic signaling may identify targets for regulating cancer metastatic potential. Raf-1 kinase inhibitor protein (RKIP) has been shown to negatively regulate signaling pathways involved in cancer progression and metastasis. RKIP may suppress metastasis of breast cancer cells by downregulating elements of the immune system. Abstract: Raf-1 kinase inhibitor protein was first identified as a negative regulator of the Raf signaling pathway. Subsequently, it was shown to have a causal role in containing cancer progression and metastasis. Early studies suggested that RKIP blocks cancer progression by inhibiting the Raf-1 pathway. However, it is not clear if the RKIP tumor and metastasis suppression function involve other targets. In addition to the Raf signaling pathway, RKIP has been found to modulate several other signaling pathways, affecting diverse biological functions including immune response. Recent advances in medicine have identified both positive and negative roles of immune response in cancer initiation, progression and metastasis. It is possible that one way that RKIP exerts its effect on cancer is by targeting an immune response mechanism. Here, we provide evidence supporting the causal role of tumor and metastasis suppressor RKIP in downregulating signaling pathways involved with immune response in breast cancer cells and discuss its potential ramification on cancer therapy. Keywords: RKIP; immunomodulator; cytokines; interferons 1. Introduction RKIP was first identified as the binding partner of Raf-1 kinase [1]. Raf-1 kinase is the activating kinase of the MEK-Erk kinase cascade that functions downstream of the membrane-associated Ras small GTPase. Upon stimulation by growth factors, GTP-bound Ras activates Raf-1. The Raf-MEK-Erk module constitutes the core mitogen signaling pathway that governs the proliferation, survival and differentiation of many different cell types [2,3]. RKIP is identical to a previously described 23 kDa phosphatidylethanolamine- binding protein (PEBP1) of the PEBP protein family. This family is a largely conserved group of proteins found in a variety of organisms, including bacteria, yeast, nematodes, plants, drosophila and mammals [4]. Due to the inhibitory effect of RKIP on Raf signaling, we Cancers 2022, 14, 3605. https://doi.org/10.3390/cancers14153605 https://www.mdpi.com/journal/cancers