Tamoxifen-Dependent Induction of <i>AGR2</i> Is Associated with Increased Aggressiveness of Endometrial Cancer Cells

<p>Tamoxifen treatment in breast cancer patients is associated with increased risk of endometrial malignancies. Significantly, higher <i>AGR2</i> expression was found in endometrial cancers that developed in women previously treated with tamoxifen compared to those who had not been exposed to tamoxifen. An association of elevated <i>AGR2</i> level with myometrial invasion occurrence and invasion depth was also found. <i>In vitro</i> analyses identified a stimulatory effect of <i>AGR2</i> on cellular proliferation. Although adverse tamoxifen effects on endometrial cells remain elusive, our work identifies elevated <i>AGR2</i> as a candidate tamoxifen-dependent mechanism of action responsible for increased incidence of endometrial cancer.</p

Quantitative Proteomic Profiling of Pleomorphic Human Sarcoma Identifies CLIC1 as a Dominant Pro-Oncogenic Receptor Expressed in Diverse Sarcoma Types

Sarcomas are rare forms of cancer with a high unmet clinical need that develop in connective tissue, such as muscle, bone, nerves, cartilage, and fat. The outcome for patients is poor, with surgery and postoperative radiotherapy the standard treatment for patients. A better understanding of the molecular pathology of sarcoma may allow for the development of novel therapeutics. There are dozens of sarcoma subtypes where there is a need for targetted therapeutics, with the most commonly studied including Ewing’s sarcoma and osteosarcoma. Here we initiate a proteomics-based target-discovery program to define “dominant” pro-oncogenic signaling targets in the most common sarcoma in adults: high-grade pleiomorphic soft tissue sarcoma. We have carried out a proteome screen using tandem mass tag isobaric labeling on three high-grade undifferentiated pleomorphic sarcoma biopsies from different tissue sites. We identified the commonly dysregulated proteins within the three sarcomas and further validated the most penetrant receptor as CLIC1, using immunohistochemistry arising from two different population cohorts representing over 300 patients. The dominant expression of CLIC1 in a broad range of human sarcomas suggests that studying this relatively unexplored signaling pathway might provide new insights into disease mechanism and facilitate the development of new CLIC1 targeted therapeutics

Quantitative Proteomic Profiling of Pleomorphic Human Sarcoma Identifies CLIC1 as a Dominant Pro-Oncogenic Receptor Expressed in Diverse Sarcoma Types

Sarcomas are rare forms of cancer with a high unmet clinical need that develop in connective tissue, such as muscle, bone, nerves, cartilage, and fat. The outcome for patients is poor, with surgery and postoperative radiotherapy the standard treatment for patients. A better understanding of the molecular pathology of sarcoma may allow for the development of novel therapeutics. There are dozens of sarcoma subtypes where there is a need for targetted therapeutics, with the most commonly studied including Ewing’s sarcoma and osteosarcoma. Here we initiate a proteomics-based target-discovery program to define “dominant” pro-oncogenic signaling targets in the most common sarcoma in adults: high-grade pleiomorphic soft tissue sarcoma. We have carried out a proteome screen using tandem mass tag isobaric labeling on three high-grade undifferentiated pleomorphic sarcoma biopsies from different tissue sites. We identified the commonly dysregulated proteins within the three sarcomas and further validated the most penetrant receptor as CLIC1, using immunohistochemistry arising from two different population cohorts representing over 300 patients. The dominant expression of CLIC1 in a broad range of human sarcomas suggests that studying this relatively unexplored signaling pathway might provide new insights into disease mechanism and facilitate the development of new CLIC1 targeted therapeutics