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Identification of regulatory crosstalks between RKIP and BRCA1 tumor suppressors in healthy tissues and cancer (breast and ovarian): Therapeutic implications

M. Rama,B. Bonavida

Published 2020 in Unknown venue

ABSTRACT

Abstract Proto-oncogenes and tumor suppressors mediate the complex molecular signaling web involved in the maintenance and control of cell growth, proliferation, and epithelial-to-mesenchymal transition, and disruptions in these pathways can often lead to cancer. To date, several tumor suppressor gene products have been characterized and their dysregulations have been associated in the pathogenesis of various human cancers. More than one tumor suppressor gene product may be expressed in the same cell, and their activities may be independent or overlapping. In addition, the regulation of tumor suppressors' expressions may be the result of crosstalks among several signaling pathways. We, therefore, have initiated a study to determine the presence or absence of a regulatory network via crosstalks of two tumor suppressor gene products expressed in normal human breast tissues and human breast carcinomas: the Raf-1 kinase inhibitor protein (RKIP) and the Breast Cancer Type 1 susceptibility protein (BRCA1). Based on their underlying common functions, we have hypothesized that the expression of these two tumor suppressors is regulated by various crosstalk-mediated signaling pathways. RKIP is a metastasis suppressor frequently expressed in normal tissues, but absent in many human cancers; it has been reported to be involved in the regulation of tumor cell proliferation and viability, invasion and metastasis, and resistance to chemo-immuno therapeutic drugs. BRCA1 is a tumor suppressor protein involved in the repair of damaged DNA, and it is frequently mutated or under-expressed in breast and ovarian cancers. To test our hypothesis, we have analyzed the reported scientific literature to extrapolate the coordinate regulatory and effector mechanisms shared between RKIP and BRCA1. Noteworthy, a broad library of studies has been published on these two proteins individually, but at present there were no reports about the potential interactions that may co-exist between the pathways that regulate RKIP and BRCA1 expressions. Interestingly, our research analyses revealed the presence of five pathways that established each crosstalk that regulate RKIP and BRCA1 expressions. These pathways with crosstalks consist of (1) signaling modules involving p53, (2) regulations of Snail and Slug, (3) beta-catenin expression, (4) Myc regulation, and (5) activation of JAK/STAT. Our delineation of these crosstalks suggested that some tumor suppressor functions in the tumor cell may be interdependent and, further, indicated the potential therapeutic targeting of one crosstalk that will also affect other related tumor suppressor gene products, thus, consequently, resulting in the enhancement of the therapeutic intervention. Our findings herein also point out to the potential of new areas of research investigations to better understand the ontogeny of tumor suppressors, their regulation in cancers, and their therapeutic implications.

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