Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop

Abstract

New cancer therapies are likely to arise from an in-depth understanding of the signaling networks influencing tumor initiation, progression and metastasis. We show a fundamental role for Src-homology 2 domain-containing phosphatase 2 (SHP2) in these processes in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancers. Knockdown of SHP2 eradicated breast tumor-initiating cells in xenograft models, and SHP2 depletion also prevented invasion in three-dimensional cultures and in a transductal invasion assay in vivo. Notably, SHP2 knockdown in established breast tumors blocked their growth and reduced metastasis. Mechanistically, SHP2 activated stemness-associated transcription factors, including v-myc myelocytomatosis viral oncogene homolog (c-Myc) and zinc finger E-box binding homeobox 1 (ZEB1), which resulted in the repression of let-7 microRNA and the expression of a set of 'SHP2 signature' genes. We found these genes to be simultaneously activated in a large subset of human primary breast tumors that are associated with invasive behavior and poor prognosis. These results provide new insights into the signaling cascades influencing tumor-initiating cells as well as a rationale for targeting SHP2 in breast cancer.

Complexity of Receptor Tyrosine Kinase Signal Processing

“…Additional example of positive feedback regulation was observed in breast tumor initiating cells (Aceto et al 2012). Src-homology 2 domain-containing phosphatase 2 (SHP2) can act as tumor promoter by facilitating RTK-induced mitogenic signaling (Ostman et al 2006).…”

“…Whereas ZEB1 drives epithelial-to-mesenchymal transition (EMT) (Schmalhofer et al 2009), c-myc induces expression of lin-28 homolog B, a repressor of microRNA biogenesis (Chang et al 2009). This leads to let-7 microRNA repression and, therefore, results in overexpression of let-7 targets, including Ras and c-Myc itself (Aceto et al 2012). Thus, SHP2-mediated positive feedback loop is required for maintenance and invasiveness of breast tumors (Aceto et al 2012).…”

“…This leads to let-7 microRNA repression and, therefore, results in overexpression of let-7 targets, including Ras and c-Myc itself (Aceto et al 2012). Thus, SHP2-mediated positive feedback loop is required for maintenance and invasiveness of breast tumors (Aceto et al 2012). Importantly, this is only one example of many in which microRNA molecules take part in signaling and transcriptional regulation downstream to RTKs (Avraham and Yarden 2012).…”

Critical role of SHP2 (PTPN11) signaling in germinal center-derived lymphoma

“…[26][27][28][29] In malignancies, SHP2 is aberrantly activated downstream of oncoproteins or by mutation. [30][31][32][33] Germline and somatic gain-of-function mutations of SHP2 are found in nearly 50% of the instances of Noonan syndrome and 35% of cases of juvenile myelomonocytic leukemia but are rarely reported in solid tumors. 34,35 Overexpression of SHP2 is also detected in samples from patients with leukemia and diffuse large B-cell lymphoma.…”

“…It was, however, robustly induced upon SHP2 re-expression and could form a SHP2-dependent positive feedback loop that enhanced the transcription factor c-Myc and oncogenic RAS expression in some solid cancers. 30 Because the well-known synergy of cMyc and CD19 aberrant expression in Eμ-Myc transgenic mice was necessary for malignant B-cell transformation, 19 we examined using immunoblot analyses, whether SHP2 commonly contributed to the reciprocal regulation of CD19 and c-Myc by transcriptional activation and subcellular localization in GC lymphoma cells. As expected, lack of SHP2 resulted in suppression of both CD19 and c-Myc protein and their activation in GC lymphoma cells ( Figure 5A), whereas CD19 knockdown had no effect on the expression of SHP2 in GC lymphoma cells but significantly inhibited its Tyr542 phosphorylation in…”