Tamoxifen resistance is one of the overarching challenges in the treatment of patients with estrogen receptor (ER)-positive breast cancer. Through a genome-wide RNA interference screen to discover genes responsible for tamoxifen resistance in vitro, we identified insulin-like growth factor binding protein 5 (IGFBP5) as a determinant of drug sensitivity. Specific knockdown of IGFBP5 by retroviral infection with short hairpin RNAexpressing cassette in MCF7 human breast cancer cells (pRS-shIGFBP5) conferred tamoxifen resistance in vitro due to concomitant loss of ERα expression and signaling. IGFBP5 expression was also reduced in MCF7 cells selected for tamoxifen resistance in culture (TAMR). Both tamoxifen-resistant MCF7-TAMR and MCF7-pRS-shIGFBP5 cells could be resensitized to drug by treatment with exogenous recombinant IGFBP5 (rIGFBP5) protein. Treatment with rIGFBP5 protein in mouse tumor xenografts reversed the in vivo tamoxifen resistance of MCF7-pRS-shIGFBP5 cell-derived tumors by reducing tumor cell proliferation. IGFBP5 immunohistochemical staining in a cohort of 153 breast cancer patients showed that low IGFBP5 expression was associated with shorter overall survival after tamoxifen therapy. Thus, IGFBP5 warrants investigation as an agent to reverse tamoxifen resistance.
Colorectal glandular-neuroendocrine mixed tumor is an uncommon entity with ill-defined clinicopathologic characteristics. We describe the clinicopathology of 23 new cases and review 67 previously reported cases. Clinically, patients (mean age, 61.9 y; male: female, 1.0:1.1) presented with a positive fecal occult blood test or visible rectal bleeding (44%), abdominal pain or change in bowel movement pattern (25%), bowel obstruction (19%), or weight loss (19%). Endoscopically, the tumors presented as a polypoid lesion (57%), a mass lesion (30%), or an ulcerating lesion (9%). Tumors were located in the right colon (56%), transverse colon (3%), and left colon (41%). Surgical resection was the treatment of choice in 83% of cases. After follow-up for an average of 20 months, the tumor-related death rate was 68%. Histologically, 42% were classified as composite tumors and 58% were classified as collision tumors. An adenoma to carcinoma, and then carcinoma to mixed tumor progression through the APC/β-catenin pathway was seen in a majority of cases. Both the glandular and the neuroendocrine components of the mixed tumor can show a spectrum of differentiation, and each component can metastasize separately regardless of its percentage volume. On the basis of the combined analysis of the pathologic spectrum and the clinical behavior of our series and previously reported cases, we propose a new classification system that reflects the differentiation of each component in colorectal glandular-neuroendocrine mixed tumor to facilitate uniform reporting and to better predict its clinical behavior.
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