Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Inhibition of SHP2 in basal-like and triple-negative breast cells induces basal-to-luminal transition, hormone dependency, and sensitivity to anti-hormone treatment

Authors: Hua Zhao, Yehenew M Agazie

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

The Src homology phosphotyrosyl phosphatase 2 (SHP2) is a positive effector of cell growth and survival signaling as well transformation induced by multiple tyrosine kinase oncogenes. Since the basal-like and triple-negative breast cancer (BTBC) is characterized by dysregulation of multiple tyrosine kinase oncogenes, we wanted to determine the importance of SHP2 in BTBC cell lines.

Methods

Short hairpin RNA-based and dominant-negative expression-based SHP2 inhibition techniques were used to interrogate the functional importance of SHP2 in BTBC cell biology. In addition, cell viability and proliferation assays were used to determine hormone dependency for growth and sensitivity to anti-estrogen treatment.

Results

We show that inhibition of SHP2 in BTBC cells induces luminal-like epithelial morphology while suppressing the mesenchymal and invasive property. We have termed this process as basal-to-luminal transition (BLT). The occurrence of BLT was confirmed by the loss of the basal marker alpha smooth muscle actin and the acquisition of the luminal marker cytokeratin 18 (CK18) expression. Furthermore, the occurrence of BLT led to estrogen receptor alpha (ERα) expression, hormone dependency, and sensitivity to tamoxifen treatment.

Conclusions

Our data show that inhibition of SHP2 induces BLT, ERα expression, dependency on estrogen for growth, and sensitivity to anti-hormone therapy. Therefore, inhibition of SHP2 may provide a therapeutic benefit in basal-like and triple-negative breast cancer.
Appendix
Available only for authorised users
Literature
1.
Rakha EA, El-Sayed ME, Reis-Filho J, Ellis IO. Patho-biological aspects of basal-like breast cancer. Breast Cancer Res Treat. 2009;113(3):411–22.CrossRefPubMed
2.
Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer. 2008;113(10):2638–45.CrossRefPubMedPubMedCentral
3.
Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 2008;14(5):1368–76.CrossRefPubMed
4.
Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R, et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell. 2010;7(3):403–17.CrossRefPubMed
5.
Bayraktar S, Gluck S. Molecularly targeted therapies for metastatic triple-negative breast cancer. Breast Cancer Res Treat. 2013;138(1):21–35.CrossRefPubMed
6.
Gastaldi S, Comoglio PM, Trusolino L. The Met oncogene and basal-like breast cancer: another culprit to watch out for? Breast Cancer Res. 2010;12(4):208.CrossRefPubMedPubMedCentral
7.
Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367–74.CrossRefPubMed
8.
Sharpe R, Pearson A, Herrera-Abreu MT, Johnson D, Mackay A, Welti JC, et al. FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo. Clin Cancer Res. 2011;17(16):5275–86.CrossRefPubMedPubMedCentral
9.
10.
Feng GS, Shen R, Heng HH, Tsui LC, Kazlauskas A, Pawson T. Receptor-binding, tyrosine phosphorylation and chromosome localization of the mouse SH2-containing phosphotyrosine phosphatase Syp. Oncogene. 1994;9(6):1545–50.PubMed
11.
Hadari YR, Kouhara H, Lax I, Schlessinger J. Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Mol Cell Biol. 1998;18(7):3966–73.CrossRefPubMedPubMedCentral
12.
Agazie YM, Movilla N, Ischenko I, Hayman MJ. The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3. Oncogene. 2003;22(44):6909–18.CrossRefPubMed
13.
Burks J, Agazie YM. Modulation of alpha-catenin Tyr phosphorylation by SHP2 positively effects cell transformation induced by the constitutively active FGFR3. Oncogene. 2006;25(54):7166–79.CrossRefPubMed
14.
Hakak Y, Hsu YS, Martin GS. Shp-2 mediates v-Src-induced morphological changes and activation of the anti-apoptotic protein kinase Akt. Oncogene. 2000;19(28):3164–71.CrossRefPubMed
15.
16.
Feng GS, Hui CC, Pawson T. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science. 1993;259(5101):1607–11.CrossRefPubMed
17.
Feng GS, Pawson T. Phosphotyrosine phosphatases with SH2 domains: regulators of signal transduction. Trends Genet. 1994;10(2):54–8.CrossRefPubMed
18.
Hartman ZR, Schaller MD, Agazie YM. The tyrosine phosphatase SHP2 regulates focal adhesion kinase to promote EGF-induced lamellipodia persistence and cell migration. Mol Cancer Res. 2013;32(35):4169–80.
19.
Zhou XD, Agazie YM. Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells. Cell Death Differ. 2008;15(6):988–96.CrossRefPubMed
20.
Aceto N, Sausgruber N, Brinkhaus H, Gaidatzis D, Martiny-Baron G, Mazzarol G, et al. Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loop. Nat Med. 2012;18(4):529–37.CrossRefPubMed
21.
Scherr M, Chaturvedi A, Battmer K, Dallmann I, Schultheis B, Ganser A, et al. Enhanced sensitivity to inhibition of SHP2, STAT5, and Gab2 expression in chronic myeloid leukemia (CML). Blood. 2006;107(8):3279–87.CrossRefPubMed
22.
Premzl A, Turk V, Kos J. Intracellular proteolytic activity of cathepsin B is associated with capillary-like tube formation by endothelial cells in vitro. J Cell Biochem. 2006;97(6):1230–40.CrossRefPubMed
23.
Debnath J, Muthuswamy SK, Brugge JS. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods. 2003;30(3):256–68.CrossRefPubMed
24.
Hollestelle A, Nagel JH, Smid M, Lam S, Elstrodt F, Wasielewski M, et al. Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat. 2010;121(1):53–64.CrossRefPubMed
25.
Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10(6):515–27.CrossRefPubMedPubMedCentral
26.
O'Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, et al. Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res. 1997;57(19):4285–300.PubMed
27.
Filmus J, Pollak MN, Cailleau R, Buick RN. MDA-468, a human breast cancer cell line with a high number of epidermal growth factor (EGF) receptors, has an amplified EGF receptor gene and is growth inhibited by EGF. Biochem Biophys Res Commun. 1985;128(2):898–905.CrossRefPubMed
28.
Zhou X, Coad J, Ducatman B, Agazie YM. SHP2 is up-regulated in breast cancer cells and in infiltrating ductal carcinoma of the breast, implying its involvement in breast oncogenesis. Histopathology. 2008;53(4):389–402.CrossRefPubMed
29.
Chavez KJ, Garimella SV, Lipkowitz S. Triple negative breast cancer cell lines: one tool in the search for better treatment of triple negative breast cancer. Breast Dis. 2010;32(1–2):35–48.PubMedPubMedCentral
30.
Jinga DC, Blidaru A, Condrea I, Ardeleanu C, Dragomir C, Szegli G, et al. MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: correlations with prognostic factors. J Cell Mol Med. 2006;10(2):499–510.CrossRefPubMed
31.
Kousidou OC, Roussidis AE, Theocharis AD, Karamanos NK. Expression of MMPs and TIMPs genes in human breast cancer epithelial cells depends on cell culture conditions and is associated with their invasive potential. Anticancer Res. 2004;24(6):4025–30.PubMed
32.
Hartman Z, Zhao H, Agazie YM. HER2 stabilizes EGFR and itself by altering autophosphorylation patterns in a manner that overcomes regulatory mechanisms and promotes proliferative and transformation signaling. Oncogene. 2013;32(35):4169–80.CrossRefPubMed
33.
Rakha EA, Ellis IO. Triple-negative/basal-like breast cancer: review. Pathology. 2009;41(1):40–7.CrossRefPubMed
34.
Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO. Prognostic markers in triple-negative breast cancer. Cancer. 2007;109(1):25–32.CrossRefPubMed
35.
Ahmed Z, Lin CC, Suen KM, Melo FA, Levitt JA, Suhling K, et al. Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity. J Cell Biol. 2013;200(4):493–504.CrossRefPubMedPubMedCentral
36.
Li J, Reed SA, Johnson SE. Hepatocyte growth factor (HGF) signals through SHP2 to regulate primary mouse myoblast proliferation. Exp Cell Res. 2009;315(13):2284–92.CrossRefPubMedPubMedCentral
37.
Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12(8):895–904.CrossRefPubMed
38.
Weigelt B, Peterse JL, van 't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5(8):591–602.CrossRefPubMed
39.
Kohrmann A, Kammerer U, Kapp M, Dietl J, Anacker J. Expression of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: New findings and review of the literature. BMC Cancer. 2009;9:188.CrossRefPubMedPubMedCentral
40.
Wang FM, Liu HQ, Liu SR, Tang SP, Yang L, Feng GS. SHP-2 promoting migration and metastasis of MCF-7 with loss of E-cadherin, dephosphorylation of FAK and secretion of MMP-9 induced by IL-1beta in vivo and in vitro. Breast Cancer Res Treat. 2005;89(1):5–14.CrossRefPubMed
41.
Engelmann K, Shen H, Finn OJ. MCF7 side population cells with characteristics of cancer stem/progenitor cells express the tumor antigen MUC1. Cancer Res. 2008;68(7):2419–26.CrossRefPubMed
42.
Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 2008;10(2):R25.CrossRefPubMedPubMedCentral
43.
Li J, Kang Y, Wei L, Liu W, Tian Y, Chen B, et al. Tyrosine phosphatase Shp2 mediates the estrogen biological action in breast cancer via interaction with the estrogen extranuclear receptor. PLoS One. 2014;9(7):e102847.CrossRefPubMedPubMedCentral
Metadata
Title
Inhibition of SHP2 in basal-like and triple-negative breast cells induces basal-to-luminal transition, hormone dependency, and sensitivity to anti-hormone treatment
Authors
Hua Zhao
Yehenew M Agazie
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1131-2

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

Satisfaction with fertility- and sexuality-related information in young women with breast cancer—ELIPPSE40 cohort

Research article

Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer

Research article

Childhood cancer mortality in Japan, 1980–2013

Research article

The prognostic value of combined TGF-β1 and ELF in hepatocellular carcinoma

Research article

Relationships between cancer pattern, country income and geographical region in Asia

Research article

Targeting mTOR/p70S6K/glycolysis signaling pathway restores glucocorticoid sensitivity to 4E-BP1 null Burkitt Lymphoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits