The CYP19A1 gene encodes aromatase, an enzyme that converts androgens into estrogens and consequently directly contributes to both the depletion of androgens and the synthesis of estrogens in several organs. Aromatase is critical for diverse biological processes such as proliferation, regulation of fat metabolism and hormone signaling. Additionally, it is also overexpressed in diverse cancers and drives hormone-dependent tumor progression and increases 17-β-estradiol (E2) within tumors and the tumor microenvironment. Although the inhibition of E2 production via aromatase inhibitors represents a major therapeutic paradigm in clinical oncology, fundamental questions regarding how cancer cells gain the capacity to overexpress aromatase remain unanswered. Multiple tissue-specific CYP19A1 promoters are known to be aberrantly active in tumors, yet how this occurs is unclear. Here, for the first time, we report that Dishevelled (DVL) proteins, which are key mediators of Wnt signaling, regulate aromatase expression in multiple breast cancer cell lines. We also report that DVL enters the nucleus and localizes to at least two different CYP19A1 promoters (pII and I.4) previously reported to drive overexpression in breast tumors and to a very distal CYP19A1 placental promoter (I.1) that remains poorly characterized. We go on to demonstrate that DVL-1 and DVL-3 loss of function leads to differential changes in various aromatase transcripts and in E2 production. The report, herein, uncovers a new regulator of CYP19A1 transcription and for the first time demonstrates that DVL, a critical mediator of WNT signaling, contributes to aberrant breast cancer-associated estrogen production.
Systemic lupus erythematous (SLE) is a systemic auto-immune disorder with a variety of presentations and wide spread organ involvement. We present a case report of a patient with an SLE exacerbation as well as concurrent rhabdomyolysis with massively elevated CPK (304,700 U/L). Though a rarely reported effect of SLE, rhabdomyolysis can be severe and potentially lethal secondary or concurrent to an acute SLE episode. This case report demonstrates the association between SLE and rhabdomyolysis, which is not well described in the current literature.
Tegmen tympani defects resulting in cerebrospinal fluid (CSF) leakage into the middle ear can lead to hearing impairment, seizures, and meningitis. While these defects can be acquired in a variety of ways, they all require prompt surgical intervention. The majority are fixed utilizing a craniotomy through the middle cranial fossa (MCF). We present a case of a tegmen tympani defect successfully repaired by a transmastoid approach utilizing Stryker bone cement in combination with DuraMatrix, and advocate this surgical approach as an effective method for treating similar cases.
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