No abstract

Persistently activated Stat3 is found in many different cancers, including Ϸ60% of breast tumors. Here, we demonstrate that a constitutively activated Stat3 transforms immortalized human mammary epithelial cells and that this oncogenic event requires the activity of matrix metalloproteinase-9 (MMP-9). By immunohistochemical analysis, we observe a positive correlation between strong MMP-9 expression and tyrosine phosphorylated Stat3 in primary breast cancer specimens. These results demonstrate a relationship between activated Stat3 and MMP-9 in breast oncogenesis.

Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on elevated JAK and FGFR activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice, by upregulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed lineage cells with elevated JAK/STAT and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.

Many endometrial adenocarcinomas, particularly those of endometrioid type, express estrogen receptors (ERs), progesterone receptors (PRs), and vimentin. This typical immunophenotype is frequently considered a standard against which others are compared when immunohistochemistry is used for differential diagnosis. We tested large numbers of endometrial cancers, enriched for high-grade tumors, to determine whether this reported immunophenotype was valid and whether expression differences between types of endometrial carcinoma could be exploited for diagnostic purposes. Immunohistochemical stains were performed on the following types of endometrial cancers using established methodology: International Federation of Gynecology and Obstetrics (FIGO) grades 1 and 2 endometrioid-42; FIGO grade 3 endometrioid-40; serous-24; clear cell-11; carcinosarcoma-9. In total, 92% of serous carcinomas expressed p16 strongly compared to weak-tomoderate expression of p16 in 7-67% of other tumors (FIGO grades 1 and 2 carcinoma and carcinosarcoma, respectively). A total of 84% of FIGO grades 1 and 2 carcinomas expressed ER compared to 9-54% of other tumors (clear cell and serous carcinomas respectively); 83% of FIGO grades 1 and 2 expressed PR compared to 11-54% of other carcinomas (carcinosarcoma and serous carcinoma, respectively). Most carcinomas were negative for monoclonal carcinoembryonic antigen (mCEA), and those that were positive showed mostly only focal membrane expression. Vimentin was expressed in nearly every tumor. Most tumors were diffusely vimentin positive, but a large range of expression patterns, from focal to diffuse and from weak to strong, was noted. Only 70% of FIGO grades 1 and 2 endometrioid carcinomas and 26% of grade 3 endometrioid carcinomas possessed the reportedly characteristic endometrial cancer immunophenotype p16 (À), ER ( þ ), PR ( þ ), mCEA (À), and vimentin ( þ ). Endometrial cancers demonstrate substantial immunophenotypic diversity that remained apparent even within groups of similar histologic subtype and grade. ER, PR, and p16 expression was more illustrative of tumor type and degree of differentiation than they were of endometrial origin. In contrast, the vimentin-positive/CEA-negative phenotype remained the most constant among all endometrial cancers.