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

Date Published: July 21, 2014

Publisher: Public Library of Science

Author(s): Jun Li, Yujia Kang, Longgang Wei, Wenjie Liu, Yingpu Tian, Baozhen Chen, Xiandong Lin, Yang Li, Gen-Sheng Feng, Zhongxian Lu, Haibin Wang.


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.

Partial Text

Recently, an increasing number of studies have found that estrogen can exert its action through a extranuclear estrogen receptor (ER) pathway [1], [2], which is thought to be required for the estrogen rapid signal, which triggers cytoplasmic kinase cascades to regulate other signals or activate transcriptional factors. The extranuclear ER pathway is involved in several crucial cellular functions such as cell proliferation, migration, secretion, and apoptosis [3], [4]. Knowledge on these novel estrogen actions is now significantly broadening our understanding of breast carcinogenesis, particularly regarding metastasis and drug resistance [5], [6]. However, mechanisms underlying rapid extranuclear responses of estrogen signal are not yet fully understood [6], [7].

The present research discovered that Shp2 mediation of the estrogen rapid extranuclear signal in breast cancer cells, and the suppression of Shp2 action blocked the development progress of the breast tumor. These results identified a novel associated protein of the extranuclear ER-initiated pathway, and suggested a novel mechanism for Shp2 action and considerably expanded the known biological effects of the extranuclear ER pathway in breast tumorigenesis.