Identification of tRNA-derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer.

Despite recent advances in targeted therapies, the molecular mechanisms driving breast cancer initiation, progression, and metastasis are minimally understood. Growing evidence indicate that transfer RNA (tRNA)-derived small RNAs (tsRNA) contribute to biological control and aberrations associated with cancer development and progression. The runt-related transcription factor 1 (RUNX1) transcription factor is a tumor suppressor in the mammary epithelium whereas RUNX1 downregulation is functionally associated with breast cancer initiation and progression. We identified four tsRNA (ts-19, ts-29, ts-46, and ts-112) that are selectively responsive to expression of the RUNX1 tumor suppressor. Our finding that ts-112 and RUNX1 anticorrelate in normal-like mammary epithelial and breast cancer lines is consistent with tumor-related activity of ts-112 and tumor suppressor activity of RUNX1. Inhibition of ts-112 in MCF10CA1a aggressive breast cancer cells significantly reduced proliferation. Ectopic expression of a ts-112 mimic in normal-like mammary epithelial MCF10A cells significantly increased proliferation. These findings support an oncogenic potential for ts-112. Moreover, RUNX1 may repress ts-112 to prevent overactive proliferation in breast epithelial cells to augment its established roles in maintaining the mammary epithelium.

Targeted sensory enrichment interventions protect against behavioral and neuroendocrine consequences of early life stress.

Both basic and clinical research support the use of tactile stimulation to rescue several neurobiobehavioral consequences that follow early life stress. Here, using a translational rodent model of the neonatal intensive care unit (NICU), we tested the individual prophylactic potential of a variety of sensory interventions including tactile (brushing pups with a paint brush to mimic maternal licking), auditory (a simulated lactating rat dam heart beat), and olfactory (a series of aroma therapy scents) stimulation. The NICU model was developed to mimic not only the reduced parental contact that sick infants receive (by isolating rat pups from their litters), but also the nosocomial infections and medical manipulations associated with this experience (by utilizing a dual lipopolysaccharide injection schedule). Each of the neurobiobehavioral consequences observed were dissociable between isolation and inflammation, or required a combined presentation ('two hits') of the neonatal stressors. Sprague-Dawley rats exposed to these early life stressors presented with sex-specific disruptions in both separation-induced ultrasonic vocalization (USV) distress calls (males & females) and juvenile social play USVs (males only). All three sensory enhancement interventions were associated with the rescue of potentiated distress calls while olfactory stimulation was protective of social vocalizations. Female rats exposed to early life stress experienced precocious puberty and shifts in the hypothalamic GnRh axis; sensory enrichment counter-acted the advanced pubertal onset. Animals that underwent the NICU protocol also displayed maturational acceleration in terms of the loss of the rooting reflex in addition to hyperalgesia, a reduced preference for a novel conspecific, blunted basal plasma corticosterone and reduced hippocampal glucocorticoid receptor expression. These alterations closely simulated the clinical effects of early life adversity in terms of disruptions in the hypothalamic pituitary "stress" axis, social communication and engagement, tactile system processing, and accelerated maturation. Moreover, sensory enrichment attenuated many of these behavioral and neurophysiological alterations, and even slowed maturation. Overall, this supports the translatability of our novel rodent model and its potential utility in understanding how brain maturation and quality of early life experiences may interact to shape the integrity of stress and sensory system development. Future work must determine the appropriate modalities and parameters (e.g. patterning, timing) for effective sensory enrichment interventions.

Complex Environmental Rearing Enhances Social Salience and Affects Hippocampal Corticotropin Releasing Hormone Receptor Expression in a Sex-Specific Manner.

Methods for understanding the neurocircuitry of ethologically relevant behaviors have advanced substantially; however renovations to standard animal laboratory housing, in the form of enhanced enrichment, have lagged behind. This is despite evidence that environmental enrichment (EE) reduces stress, stereotypy, and promotes healthy species typical behaviors. While many scientists express interest for increased EE as a standard for animal caging systems, there are concerns that its effects on brain, behavior, and cognition are not well characterized. In the present study, male and female Sprague-Dawley rats were housed for six weeks in either EE, Colony Nesting (CN), or Standard Housing (SD) conditions. We show that adolescent exposure to environmental complexity changed the dynamics of social interactions, sensory processing, and underlying basal stress neurocircuitry, in a sex- and enrichment-type-dependent manner. Specifically, EE and CN increased prosocial engagement and the social saliency of male and female rats while the profile of hippocampal Crhr2 expression was affected only in EE males. Hippocampal Crh was associated with anxiety-like behavior in SD males - this did not extend to EE or CN groups, nor to females. Observations such as these are an important consideration for the validity of translational research investigating the neurocircuitry of stress resiliency, and for understanding the mechanisms of psychiatric disorders. Future work must focus on characterizing how individual environmental enhancements (e.g. novelty, social enrichment, physical activity) shape phenotypic differences, how they vary as a function of species, strain and sex, and (if warranted) how to meaningfully implement this knowledge into biomedical research designs.