Translational Implications of Dysregulated Pathways and microRNA Regulation in Quadruple-Negative Breast Cancer

Abstract

Triple-negative breast cancers (HER2−, ER−, PR−) continue to present a unique treatment challenge and carry unfavorable prognoses. The elucidation of novel therapeutic targets has necessitated the re-evaluation of stratification approaches to best predict prognosis, treatment response and theranostic and prognostic markers. Androgen receptor expression and function have important implications on proliferation, tumor progression, immunity and molecular signaling in breast cancer. Accordingly, there has been increasing support for classification of androgen receptor-negative triple-negative breast cancer or quadruple-negative breast cancer (QNBC). QNBC has unique molecular, signaling and expression regulation profiles, particularly those affected by microRNA regulatory networks. MicroRNAs are now known to regulate AR-related targets and pathways that are dysregulated in QNBC, including immune checkpoint inhibitors (ICIs), SKP2, EN1, ACSL4 and EGFR. In this review, we explore and define the QNBC tumor subtype, its molecular and clinical distinctions from other subtypes, miRNA dysregulation and function in QNBC, and knowledge gaps in the field. Potential insights into clinical and translational implications of these dysregulated networks in QNBC are discussed.

MicroRNAs within the Basal-like signature of Quadruple Negative Breast Cancer impact overall survival in African Americans

“…The versatility of miRNAs at physiological and pathological levels makes them indispensable factors for many types of cancer, including mammary cancers. This is corroborated by the fact that they have a function in racial cancer disparities based on diagnosis, prognosis, disease progression, and response to various therapeutic modalities 25 . For instance, mir-655 expression positively correlates with COX-2 in genetically diverse breast cancer cells grown as spheroids, thereby linking it with stem-like cells 26 .…”

MicroRNAs within Basal-Like Signature of Quadruple Negative Breast Cancer Impact Overall Survival in African Americans

“…The versatility of miRNAs at physiological and pathological levels makes them indispensable factors for many types of cancer, including mammary cancers. This is corroborated by the fact that they have a function in racial cancer disparities based on diagnosis, prognosis, disease progression, and response to various therapeutic modalities (23). For instance, mir-655 expression positively correlates with COX-2 in genetically diverse breast cancer cells grown as spheroids, thereby linking it with stem-like cells (24).…”

ACSL4: biomarker, mediator and target in quadruple negative breast cancer

“…Lehmann et al [40] have reported four similar subdivisions. Due to the fact that the LAR subcategory, which is unique in expressing androgen receptor (AR), is significantly different from the other three subcategories, AR-negative TNBCs have been grouped together in a category referred to as quadruple negative breast cancer (QNBC) [41][42][43]. As has previously been reported, ACSL4 overexpression is a defining characteristic of QNBC [24].…”