Supporting Direct Breastfeeding for a Tracheostomy-Dependent Extremely Premature Infant: A Case Study.

INTRODUCTION: The benefits of human milk for preterm infants are well documented. Complex medical conditions can limit the extremely premature infant's ability to breastfeed and to receive human milk directly, yet these vulnerable infants may benefit most from receiving it. MAIN ISSUE: Extremely preterm infants are at risk for infections, digestive challenges, and chronic lung disease, and occasionally require a tracheostomy to facilitate weaning from mechanical ventilation. There is a risk of aspiration when orally feeding a child with a tracheostomy. This case study describes a tertiary neonatal team supporting a family's direct breastfeeding goal in an extremely premature infant with a diagnosis of bronchopulmonary dysplasia requiring a tracheostomy. MANAGEMENT: Initially, the infant participant (born at 24 weeks and 3 days of gestation, with a birthweight of 540 g) was gavage fed with human milk. The interdisciplinary team collaborated with the family to guide the infant's feeding goals, providing positive oral stimulation with soothers, oral immune therapy, and frequent skin-to-skin contact to prepare for future oral feeding. Within a month of the tracheotomy procedure, oral feeding was initiated, and direct breastfeeding with the tracheostomy tubing in place was achieved at 50 weeks and 1 day of age as a primary source of nutrition. CONCLUSION: The open dialogue between the family and healthcare team was the foundation for trialing direct breastfeeding for an extremely premature infant with a tracheostomy. While direct breastfeeding of full-term infants with tracheostomies has been previously described in the literature, this is the first case study of an extremely premature infant with a tracheostomy transitioning to direct breastfeeding.

Phosphorylation of activation function-1 regulates proteasome-dependent nuclear mobility and E6-associated protein ubiquitin ligase recruitment to the estrogen receptor beta.

The ubiquitin-proteasome pathway has been recognized as an important regulator in the hormonal response by estrogen receptor (ER) alpha, but its impact on ERbeta function is poorly characterized. In the current study, we investigated the role of the ubiquitin-proteasome pathway in regulating ERbeta activity and identified regulatory sites within the activation function (AF)-1 domain that modulate ERbeta ubiquitination and nuclear dynamics in a hormone-independent manner. Although both ERalpha and ERbeta were dependent on proteasome function for their maximal response to estrogen, they were regulated differently by proteasome inhibition in the absence of hormone, an effect shown to be dependent on their respective AF-1 domain. Given the role of AF-1 phosphorylation to regulate ER activity, we found that sequential substitutions of specific serine residues contained in MAPK consensus sites conferred transcriptional activation of ERbeta in a proteasome-dependent manner through reduced ubiquitination and enhanced accumulation of mutant receptors. Specifically, serines 94 and 106 within ERbeta AF-1 domain were found to modulate subnuclear mobility of the receptor to transit between inactive clusters and a more mobile state in a proteasome-dependent manner. In addition, cellular levels of ERbeta were regulated through these sites by facilitating the recruitment of the ubiquitin ligase E6-associated protein in a phosphorylation-dependent manner. These findings suggest a role for ERbeta AF-1 in contributing to the activation-degradation cycling of the receptor through a functional clustering of phosphorylated serine residues that cooperate in generating signals to the ubiquitin-proteasome pathway.

Selective hormone-dependent repression of estrogen receptor beta by a p38-activated ErbB2/ErbB3 pathway.

Deregulated signaling of ErbB2 receptor tyrosine kinase is often associated with hormone resistance in estrogen receptor alpha (ERalpha)-positive breast cancers, establishing a relationship between ErbB2 and ERalpha pathways. Although ERalpha and ERbeta are expressed in many breast cancer cells, the response of ERbeta to ErbB2 signaling is less well defined. In the present study, we demonstrate that ERbeta activity can be modulated by ErbB2 signaling in ER-expressing breast cancer cells. The estrogen-dependent transcriptional activity of ERbeta was altered in a manner similar to ERalpha by either activation of ErbB2/ErbB3 signaling by growth factor heregulin beta or expression of a constitutively active mutant of ErbB2. However, as opposed to ERalpha, the p38 MAPK pathway was found to be involved in liganded ERbeta repression activity by ErbB2 signaling and in regulating estrogen-responsive promoter occupancy by ERbeta. The repression in ERbeta response to hormone was dependent upon its AF-1 domain which includes serines 106 and 124, two phosphorylation target sites for Erk that we previously showed to be involved in SRC-1 recruitment to ERbeta. Substitution of these two serines by aspartic acid residues abolished the repression of ERbeta by activated ErbB2/ErbB3. Moreover, expression of SRC-1 also relieved the inhibition of ERbeta in heregulin-treated cells. Our study demonstrates a functional coupling between ERbeta and ErbB receptors and outlines the differential role of the AF-1 region in the regulation of the estrogen-dependent cell growth and activity of both estrogen receptors in response to growth factor signaling.