Deregulation of Stat5 expression and activation causes mammary tumors in transgenic mice

Abstract

Members of the signal transducers and activators of transcription (Stat) family regulate essential cellular growth and survival functions in normal cells and have also been implicated in tumorigenesis. We have studied the potential role of Stat5 in mammary tumorigenesis by targeting Stat5 variants to the mammary gland of transgenic mice using regulatory sequences of the ␤-lactoglobulin gene. Mammary-directed expression of the wild-type Stat5, constitutively activated Stat5 and carboxyl-terminally truncated dominant negative Stat5 forms resulted in mammary tumors with incidence rates of up to 22% and latency periods of 8 -12 months. Undifferentiated carcinomas most frequently occurred in mice expressing the carboxyl-terminally truncated Stat5. The more differentiated papillary and micropapillary adenocarcinomas were primarily found in mice overexpressing the native and constitutively active transgenes. Higher levels of translation initiation factor 4E (eIF4E) and cyclin D1 expression but lower levels of activated Stat3 were found in tumors of mice expressing the constitutively active Stat5 when compared to mice expressing the wild-type or truncated forms. A higher expression of the estrogen receptor (ER␣) was observed in carcinomas compared to other phenotypes. The ability of both forms of Stat5, the transactivating form and the dominant negative form, to participate in oncogenesis indicates that there is more than one mechanism by which Stat5 contributes to this process. The transactivation function of Stat5 is involved in the determination of tumors with a more differentiated phenotype.

Nuclear Janus-Activated Kinase 2/Nuclear Factor 1-C2 Suppresses Tumorigenesis and Epithelial-to-Mesenchymal Transition by Repressing Forkhead Box F1

“…The role of prolactin in mammary gland development makes this hormone a candidate factor in the control of initiation and progression of breast cancer. However, it remains controversial whether prolactin promotes tumor growth (2)(3)(4)(5) or suppresses invasiveness by upholding a differentiated state (6)(7)(8). The issue is complicated by the presence of multiple signaling pathways downstream of the prolactin receptor.…”

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα+ tumorigenesis

“…Mice engineered for persistent PrlR signaling display significantly increased incidences of ERa þ mammary tumors. 7,8 However, the natural processes that govern the pro-oncogenic potential of PrlR signaling remain largely unknown.…”

Mammary Tumorigenesis following Transgenic Expression of a Dominant Negative CHK2 Mutant

“…2). Micropapillary tumors are characterized by epithelial cells with short papillae lacking a distinct fibrovascular stalk, an unusual histology that has been previously described in STAT 5 and CK2a-driven mammary tumors (18,19) and is clearly distinguishable from that of the well-studied erbB2-driven or cmyc-driven mammary tumor models (20,21). A subset of CHK2-D347A-driven tumors had other histologies, including epithelioid, spindle cell, intermediate cell, glandular, and adenosquamous.…”