The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation. The epithelial-mesenchymal transition (EMT) is essential to germ layer formation and cell migration in the early vertebrate embryo. EMT is aberrantly reactivated under pathological conditions, including fibrotic disease and cancer progression. In the latter process, EMT is known to promote invasion and metastatic dissemination of tumor cells. EMT is orchestrated by a variety of embryonic transcription factors called EMT inducers. Among these, the TWIST and ZEB proteins are known to be frequently reactivated during tumor development. We here report in vitro and in vivo observations demonstrating that activation of these factors fosters cell transformation and primary tumor growth by alleviating key oncosuppressive mechanisms, thereby minimizing the number of events required for acquisition of malignant properties. In a model of breast cancer, cooperation between a single EMT inducer and a single mitogenic oncoprotein is sufficient to transform mammary epithelial cells into malignant cells and to drive the development of aggressive and undifferentiated tumors. Overall, these data underscore the oncogenic role of embryonic transcription factors in initiating the development of poor-prognosis neoplasms by promoting both cell transformation and dedifferentiation.