Protein tyrosine phosphatase ε increases the risk of mammary hyperplasia and mammary tumors in transgenic mice

Abstract

Accurate phosphorylation of tyrosine residues in proteins plays a central role in regulation of cellular function. Although connections between aberrant tyrosine kinase activity and malignancy are well-established, signi®cantly less is known about the roles of protein tyrosine phosphatases (PTPases) in tumorigenesis. We have previously shown that the transmembranal form of PTPase Epsilon (PTPe) is upregulated in mouse mammary tumors initiated speci®cally by ras or neu, suggesting that PTPe may play a role in transformation by these two oncogenes. In order to test this notion in vivo, we created transgenic mice that express elevated levels of PTPe in their mammary epithelium by use of the MMTV promoter/enhancer. Following several cycles of pregnancy female MMTV-PTPe mice uniformly developed pronounced and persistent mammary hyperplasia which was accompanied by residual milk production. Solitary mammary tumors were often detected secondary to mammary hyperplasia. The sporadic nature of the tumors, the long latency period prior to their development, and low levels of transgene expression in the tumors indicate that PTPe provides a necessary, but insu cient, signal for oncogenesis. The results provide genetic evidence that PTPe plays an accessory role in production of mammary tumors in a manner consistent with its upregulation in mammary tumors induced by ras or neu.

Generation of novel cytoplasmic forms of protein tyrosine phosphatase epsilon by proteolytic processing and translational control

“…This ®nding suggests that tm-PTPe may participate in molecular processes by which ras or neu speci®cally transform mammary epithelium. In agreement with this interpretation, overexpression of tm-PTPe in mouse mammary epithelium promotes mammary hyperplasia and associated neoplasia (Elson, 1999). tm-PTPe can down-regulate insulin receptor signaling in certain types of cultured cells (Moller et al, 1995), a function which is not shared with cyt-PTPe due to the predominantly non-membrane localization of the latter (JN Andersen, A Elson, R Lammers, J Romer, JT Clausen, KB Moller and NPH Moller, manuscript submitted for publication).…”

“…Localization as in c was observed in cells expressing a PTPe molecule whose translation starts at the ATG3 codon and which is similar in mass to p65 (not shown) In a separate series of experiments we examined associations between PTPe and the adaptor molecule Grb2. Grb2 binds either tm-PTPe or cyt-PTPe molecules via its SH2 domain in an interaction which requires tyrosine phosphorylation of PTPe (Toledano-Katchalski and Elson, 1999). This association can be detected in several cell types due to basal phosphorylation of PTPe by resident tyrosine kinases.…”

Expression of protein tyrosine phosphatase alpha (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo

“…Therefore, it is possible that high RPTPa expression in a subset of tumors is a remnant of an earlier disease stage, where it may have contributed to initiation, or early progression, but is lost at later stages in favor of more aggressive progression events. Interestingly, transgenic expression of PTPe enhances the incidence of mammary malignancy, but the ensuing tumors express very low PTPe levels (Elson, 1999), consistent with a speci®c role of this PTP in early stages of progression only. Ultimately, transgenic models may be useful to further dissect the potential contribution of RPTPa to tumor initiation and/or progression.…”

“…In primary human tumors, membrane PTP activity correlates with the presence of tumor positive axillary lymph nodes, whereas cytosolic activity correlates with the mitotic index (Ottenho -Kal et al, 1995). Increased PTPe levels were observed in mouse tumors induced by HER2/neu or v-Ha-Ras, but not by c-myc or int-2 (Elson and Leder, 1995b), and constitutive PTPe expression increases the risk of mammary tumor development in transgenic mice (Elson, 1999).…”

“…However, Sos recruitment by Grb2 to RPTPa is not the only way in which RPTPa may a ect Ras signaling; for instance, RPTPa may sequester Grb2 away from Sos; or Grb2 may recruit Grb2-bound docking proteins for dephosphorylation by RPTPa. Second, overexpression of RPTPa is observed in advanced human colon carcinoma (Tabiti et al, 1995), and a closely related PTP, RPTPe, is implicated in mouse mammary tumorigenesis (Elson and Leder, 1995b) (Elson, 1999). Third, RPTPa is an important regulator of SFK activity, by controlling dephosphorylation of the carboxy-terminal negative regulatory Y530 site of cSrc.…”