Triple-negative breast cancer (TNBC) is a common and aggressive subtype of breast cancer that is refractory to current targeted therapies. A major barrier to developing TNBC therapies is the paucity in our understanding of the molecular drivers of TNBC. Identifying the signaling networks whose dysregulation drives TNBC would have enormous impact on our understanding of the disease and how we treat afflicted patients. Recently, we discovered a tumor suppressor role for the PTPN12 tyrosine phosphatase in TNBC (Sun et al, Cell 2011). Our data indicate PTPN12 is compromised in many epithelial cancers including more than 70% of TNBCs. Loss of endogenous PTPN12 leads to hyper-activation of specific proto-oncogenic tyrosine kinases and consequent transformation of human mammary epithelial cells (HMECs). PTPN12 is frequently inactivated in TNBC by post-transcriptional mechanisms, and restoring PTPN12 function dramatically impairs tumor progression and metastasis in TNBCs. These studies suggest PTPN12 functions as a suppressor of human TNBC. However, the pathways controlling PTPN12 function and the mechanisms by which PTPN12 suppresses epithelial cancers like TNBC are poorly understood. We propose to define the molecular framework of the PTPN12 tumor suppressor network and exploit these mechanisms as therapeutic entrypoints in TNBC. Specifically, we will address the following critical questions:
Aim 1 : How is the PTPN12 tumor suppressor protein hyper-degraded in TNBC? Our preliminary data suggest that PTPN12 is prominently inactivated in TNBC at the protein level by hyper-degradation. Our evidence indicates PTPN12 is ubiquitylated and highly unstable. We will exploit newly developed genetic screening tools that we developed to identify components of the regulatory network controlling PTPN12 ubiquitination and stability, and test their role in cellular transformation and TNBC survival.
Aim 2 : Can reactivation of PTPN12 in murine and human triple-negative breast cancers suppress tumor progression in vivo? PTPN12 protein is frequently lost in human TNBCs, and the tumorigenic and metastatic properties of PTPN12-deficient TNBC are impaired in response to restoring PTPN12. We will develop and test complementary models of PTPN12-deficient human and murine TNBC, and use these models to delineate the mechanisms of PTPN12 anti-TNBC properties.
Aim 3 : How does PTPN12 dysfunction regulate survival of TNBCs? Restoring PTPN12 expression is cytotoxic and impairs TNBC tumor progression, suggesting PTPN12 inhibits key survival pathways in TNBCs. Mechanistically, loss of PTPN12 leads to combined hyper-activation of the tyrosine kinases (TKs) cMET and PDGFR-?. We will test the hypothesis that PTPN12 impairs TNBC progression by combined inhibition of cMET and PDGFR-?, and these PTPN12-regulated TKs cooperate to confer tumor survival in PTPN12- deficient TNBCs.
Our proposal aims to develop new strategies to combat a common and aggressive subtype of human breast cancer (triple-negative breast cancer, or TNBC). We recently discovered a major regulator of TNBC called the PTPN12 tumor suppressor, and have now shown that (a) PTPN12 is frequently inactivated in TNBC, and (b) restoring the function of PTPN12 impairs TNBC tumor cell survival, tumor progression, and metastasis. We propose to discover a molecular framework for the PTPN12 tumor suppressor pathway, to develop new approaches to restore PTPN12 function, and to test these strategies in newly developed pre-clinical models of TNBC.
| Hsu, Tiffany Y-T; Simon, Lukas M; Neill, Nicholas J et al. (2015) The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature 525:384-8 |
| Izhar, Lior; Adamson, Britt; Ciccia, Alberto et al. (2015) A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP-Dependent Recruitment of Transcription Factors. Cell Rep 11:1486-500 |
| Mahamdallie, Shazia S; Hanks, Sandra; Karlin, Kristen L et al. (2015) Mutations in the transcriptional repressor REST predispose to Wilms tumor. Nat Genet 47:1471-4 |
| Miao, Qi; Ku, Amy T; Nishino, Yudai et al. (2014) Tcf3 promotes cell migration and wound repair through regulation of lipocalin 2. Nat Commun 5:4088 |
| Karlin, Kristen L; Mondal, Gourish; Hartman, Jessica K et al. (2014) The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor. Cell Rep 9:1318-32 |
