A Population Description of Young Women with Breast Cancer in Newfoundland and Labrador.

It has been well established in the literature that young women tend to carry more aggressive subtypes of breast cancer than their older-aged counterparts. The objective of this study was to describe the characteristics and outcomes of young women with breast cancer. In this retrospective analysis, data were collected for women under the age of 40 years who were diagnosed with breast cancer between 2008 and 2018 in the province of Newfoundland and Labrador. Specifically, data were collected on demographics, staging, pathological characteristics, treatment, and survival outcomes for young women with this disease. Results demonstrate that most of these women were diagnosed between the age of 35 and 39 years (91.2%). Most women presented with early-stage disease (stage I and II-66.4%), while 24% were stage III and 9.6% presented with stage IV metastatic disease. The prevalence of hormone-receptor-positive disease represented 41.9% of the cohort, with triple-negative and HER2+ measuring 27.7% and 30.4%, respectively. Five-year disease-free survival was 80.5% and overall survival was 82.7%. These findings provoke discussion regarding the intersecting roles of genetics, environment, and lifestyle in a region with some of the highest rates of malignancy in the country.

Mapping and functional characterization of murine kidney injury molecule-1 proteolytic cleavage site.

Kidney injury molecule-1 (KIM-1), also known as T cell immunoglobulin and mucin domain 1 (TIM-1), is a transmembrane glycoprotein expressed on proximal tubule epithelia during acute kidney injury (AKI). Extracellular domain of KIM-1 undergoes spontaneous and activated ectodomain shedding into urine and blood via metalloproteases. Soluble KIM-1 (blood and urinary) is a reliable clinical biomarker of proximal tubular injury, but the biological significance of shedding remains unknown. The aim of this study was to identify the specific shedding enzyme and the proteolytic cleavage site of murine KIM-1, followed by the characterization of its functional relevance. In this regard, isoleucine (I) I202 was identified as the potential cleavage site. Mutation of isoleucine I202 to glutamine (I202Q) or alanine (I202A) significantly reduced both constitutive and induced KIM-1 shedding and ultimately efferocytosis. It was also uncovered that ADAM10 is the major sheddase that mediates the proteolytic cleavage of murine KIM-1. In addition, ADAM10-induced KIM-1 shedding was required for efficient phagocytic clearance of apoptotic cells. Importantly, the findings that the addition of exogenous shed KIM-1 rescued the phagocytic impairment suggest that shed KIM-1 is capable of modulating efferocytosis of apoptotic bodies and could represent a potential functional role of the soluble ectodomain KIM-1 during AKI.

Tctex-1, a novel interaction partner of Kidney Injury Molecule-1, is required for efferocytosis.

Kidney injury molecule-1 (KIM-1) is a phosphatidylserine receptor that is specifically upregulated on proximal tubular epithelial cells (PTECs) during acute kidney injury and mitigates tissue damage by mediating efferocytosis (the phagocytic clearance of apoptotic cells). The signaling molecules that regulate efferocytosis in TECs are not well understood. Using a yeast two-hybrid screen, we identified the dynein light chain protein, Tctex-1, as a novel KIM-1-interacting protein. Immunoprecipitation and confocal imaging studies suggested that Tctex-1 associates with KIM-1 in cells at baseline, but, dissociates from KIM-1 within 90 min of initiation of efferocytosis. Interfering with actin or microtubule polymerization interestingly prevented the dissociation of KIM-1 from Tctex-1. Moreover, the subcellular localization of Tctex-1 changed from being microtubule-associated to mainly cytosolic upon expression of KIM-1. Short hairpin RNA-mediated silencing of endogenous Tctex-1 in cells significantly inhibited efferocytosis to levels comparable to that of knock down of KIM-1 in the same cells. Importantly, Tctex-1 was not involved in the delivery of KIM-1 to the cell-surface. On the other hand, KIM-1 expression significantly inhibited the phosphorylation of Tctex-1 at threonine 94 (T94), a post-translational modification which is known to disrupt the binding of Tctex-1 to dynein on microtubules. In keeping with this, we found that KIM-1 bound less efficiently to the phosphomimic (T94E) mutant of Tctex-1 compared to wild type Tctex-1. Surprisingly, expression of Tctex-1 T94E did not influence KIM-1-mediated efferocytosis. Our studies uncover a previously unknown role for Tctex-1 in KIM-1-dependent efferocytosis in epithelial cells.