Tyrosine Phosphatase Shp2 Mediates the Estrogen Biological Action in Breast Cancer via Interaction with the Estrogen Extranuclear Receptor

Abstract

The extranuclear estrogen receptor pathway opens up novel perspectives in many physiological and pathological processes, especially in breast carcinogenesis. However, its function and mechanisms are not fully understood. Herein we present data identifying Shp2, a SH2-containing tyrosine phosphatase, as a critical component of extranuclear ER pathway in breast cancer. The research checked that the effect of Shp2 on the tumor formation and growth in animal model and investigated the regulation of Shp2 on the bio-effect and signaling transduction of estrogen in breast cancer cell lines. The results showed that Shp2 was highly expressed in more than 60% of total 151 breast cancer cases. The inhibition of Shp2 activity by PHPS1 (a Shp2 inhibitor) delayed the development of dimethylbenz(a)anthracene (DMBA)-induced tumors in the rat mammary gland and also blocked tumor formation in MMTV-pyvt transgenic mice. Estradiol (E2) stimulated protein expression and phosphorylation of Shp2, and induced Shp2 binding to ERα and IGF-1R around the membrane to facilitate the phosphorylation of Erk and Akt in breast cancer cells MCF7. Shp2 was also involved in several biological effects of the extranuclear ER-initiated pathway in breast cancer cells. Specific inhibitors (phps1, phps4 and NSC87877) or small interference RNAs (siRNA) of Shp2 remarkably suppressed E2-induced gene transcription (Cyclin D1 and trefoil factor 1 (TFF1)), rapid DNA synthesis and late effects on cell growth. These results introduced a new mechanism for Shp2 oncogenic action and shed new light on extranuclear ER-initiated action in breast tumorigenesis by identifying a novel associated protein, Shp2, for extranuclear ER pathway, which might benefit the therapy of breast cancer.

Shp2 Associates with and Enhances Nephrin Tyrosine Phosphorylation and Is Necessary for Foot Process Spreading in Mouse Models of Podocyte Injury

“…In order to test available small-molecule inhibitors of Shp2 as a potential therapeutic modality, we perfused 2-month-old mice with NSC87877, a specific inhibitor of Shp2 phosphatase activity (41)(42)(43). The mice were perfused with NSC87877 30 min prior to perfusion of protamine sulfate.…”

PTPN11/SHP2 negatively regulates growth in breast epithelial cells: implications on tumorigenesis

“…Knockdown of PTPN11/SHP2 in luminal A cell line, such as T47D, has been reported to decrease migration rate and EMT (Sun et al 2017), while inhibition of PTPN11/SHP2 in luminal B cell line, MCF7, decreases cell growth (Li et al 2014). This is in accordance with the oncogenic function of PTPN11/SHP2.…”

Increased Cell Proliferation by Various Doses of Xenoestrogen in MFC-7 Cell Through Tyrosine Phosphatase Shp2

“…Our previous studies suggested that tyrosine phosphatase Shp2 mediates the estrogen biological action in breast cancer [29]. Therefore, in present study, we made further investigation into Xenoestrogen exposure in proliferative activity in MCF7 cells by both MTT assay (cell proliferative activity) and western blot (tyrosine phosphatase Shp2 level).…”

“…Recently, a new estrogen membrane receptor Shp2 was identified. Tyrosine phosphatase Shp2 has latterly been shown to play a critical role in estrogen signalling and functions in breast cancer development [27][28][29][30]. It was also found that Shp2 appears to regulate the Ras-MAPK、 PKB/AKT pathway while affecting extracellular-regulated kinase activation by estrogen [29,30], which can bind to the estrogen receptor and IGF-1 membrane receptor, mediated the regulation of estrogen membrane receptor signaling in breast cancer.…”