Exploring neurotransmitters and their receptors for breast cancer prevention and treatment

While psychological factors have long been linked to breast cancer pathogenesis and outcomes, accumulating evidence is revealing how the nervous system contributes to breast cancer development, progression, and treatment resistance. Central to the psychological-neurological nexus are interactions between neurotransmitters and their receptors expressed on breast cancer cells and other types of cells in the tumor microenvironment, which activate various intracellular signaling pathways. Importantly, the manipulation of these interactions is emerging as a potential avenue for breast cancer prevention and treatment. However, an important caveat is that the same neurotransmitter can exert multiple and sometimes opposing effects. In addition, certain neurotransmitters can be produced and secreted by non-neuronal cells including breast cancer cells that similarly activate intracellular signaling upon binding to their receptors. In this review we dissect the evidence for the emerging paradigm linking neurotransmitters and their receptors with breast cancer. Foremost, we explore the intricacies of such neurotransmitter-receptor interactions, including those that impinge on other cellular components of the tumor microenvironment, such as endothelial cells and immune cells. Moreover, we discuss findings where clinical agents used to treat neurological and/or psychological disorders have exhibited preventive/therapeutic effects against breast cancer in either associative or pre-clinical studies. Further, we elaborate on the current progress to identify druggable components of the psychological-neurological nexus that can be exploited for the prevention and treatment of breast cancer as well as other tumor types. We also provide our perspectives regarding future challenges in this field where multidisciplinary cooperation is a paramount requirement

La importancia de los miARNs en la regulación y progresión tumoral de células de cáncer de mama

"Las secuencias más estudiadas del genoma humano son aquellas correspondientes a los genes codificantes de proteínas que representan alrededor del 2% total del ADN de las células humanas; el llamado ADN “basura”, ha tomado relevancia dado que la porción no codificante del genoma tiene una función crucial en la modulación de diversos procesos fisiológicos y patológicos, que van desde el desarrollo embrionario hasta la progresión de neoplasias. Los miARNs desempeñan un papel fundamental en la regulación de la expresión genética, al inhibir la traducción del ARN mensajero a proteína; participan en diversos procesos celulares tales como la diferenciación celular, proliferación y apoptosis, por lo que la desregulación de un miARN o grupo de miARNs puede llegar a tener un impacto directo sobre la homeostasis celular y favorecer el desarrollo de múltiples enfermedades. Debido al creciente número de publicaciones relacionadas a la función de los miARNs y su probable papel en la fisiopatología del cáncer de mama, se propuso, en el presente trabajo, explorar la participación de los miARNs en la patogénesis y progresión tumoral de las células de cáncer de mama, así como el papel regulatorio postranscripcional de varios de los miARNs involucrados en las vías celulares relacionadas al cáncer"

PCBP1 Regulates LIFR Through FAM3C to Maintain Breast Cancer Stem Cell Self-Renewal and Invasiveness

The poly(rC) binding protein 1 gene (PCBP1) encodes the heterogenous nuclear ribonucleoprotein E1 (hnRNPE1), a nucleic acid-binding protein that plays a tumor-suppressive role in mammary epithelial cells by regulating phenotypic plasticity and cell fate. Following the loss of PCBP1 function, the FAM3C gene (encoding the Interleukin-like EMT inducer, or “ILEI” protein) and the leukemia inhibitory factor receptor (LIFR) gene are upregulated. Interaction between FAM3C and LIFR in the extracellular space induces phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Overexpression and/or hyperactivity of STAT3 has been detected in 40% of breast cancer cases and is associated with a poor prognosis. Herein, we characterize a “feed-forward” mechanism that regulates the expression of LIFR in response to FAM3C/LIFR/STAT3 signaling in mammary epithelial cells. We show that the loss of PCBP1 expression upregulates LIFR transcription through activity at the LIFR promoter. We also show that LIFR transcription is affected by modulation of FAM3C expression levels. Additionally, our bioinformatic analysis reveals a signature of transcriptional regulation associated with the FAM3C/LIFR interaction and identifies the TWIST1 transcription factor as a downstream effector that participates in the maintenance of LIFR expression. Finally, we characterize the effect of LIFR expression in cell-based experiments using both mouse and human mammary epithelial cells. Our experiments demonstrate the promotion of invasion, migration, and self-renewal of breast cancer stem cells (BCSCs) following increased LIFR expression, which is consistent with previous studies linking LIFR expression to tumor initiation and metastasis in mammary epithelial cells