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Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Breast Cancer | Primary research

TGF-β1 stimulates epithelial–mesenchymal transition and cancer-associated myoepithelial cell during the progression from in situ to invasive breast cancer

Authors: Li Wang, Cong Xu, Xia Liu, Yang Yang, Lu Cao, Guomin Xiang, Fang Liu, Shuling Wang, Jing Liu, Qingxiang Meng, Jiao Jiao, Yun Niu

Published in: Cancer Cell International | Issue 1/2019

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Abstract

Background

The progression of ductal carcinoma in situ (DCIS) into invasive ductal carcinoma (IDC) is prevented by normal breast myoepithelial cells. Studies have suggested that EMT-associated genes were enriched in IDC in contrast to DCIS. This paper explored the relationship and potential mechanism between myoepithelial cells and EMT-associated genes in facilitating the transformation from DCIS to breast cancer.

Methods

EMT markers and myoepithelial phenotypic markers in IDC, DCIS, and healthy breast tissue were characterized using immunohistochemical assay. Both in vivo and in vitro models were created to mimic the various cell–cell interactions in the development of invasive breast cancer.

Results

We found that EMT markers were more abundant in invasive carcinomas than DCIS and adjacent normal breast tissue. Meanwhile, TGF-β1 regulated the morphology of MCF-7 (epithelial cells substitute) migration and EMT markers during the transformation from DCIS to invasive breast cancer. Additionally, TGF-β1 also regulated invasion, migration and cytokines secretion of MDA-MB-231 (myoepithelial cells substitute) and epithelial cells when co-cultured with MCF-7 both in vitro and in vivo.

Conclusions

In conclusion, these findings demonstrated that both EMT phenotypes and cancer-associated myoepithelial cells may have an impact on the development of invasive breast cancer.
Literature
1.
go back to reference Fu F, Gilmore RC, Jacobs LK. Ductal carcinoma in situ. Surg Clin North Am. 2018;98(4):725–45.CrossRef Fu F, Gilmore RC, Jacobs LK. Ductal carcinoma in situ. Surg Clin North Am. 2018;98(4):725–45.CrossRef
2.
go back to reference Cowell CF, Weigelt B, Sakr RA, Ng CK, Hicks J, King TA, Reis-Filho JS. Progression from ductal carcinoma in situ to invasive breast cancer: revisited. Mol Oncol. 2013;7(5):859–69.CrossRef Cowell CF, Weigelt B, Sakr RA, Ng CK, Hicks J, King TA, Reis-Filho JS. Progression from ductal carcinoma in situ to invasive breast cancer: revisited. Mol Oncol. 2013;7(5):859–69.CrossRef
3.
go back to reference Allen MD, Thomas GJ, Clark S, et al. Altered microenvironment promotes progression of preinvasive breast cancer: myoepithelial expression of αvβ6 integrin in DCIS identifies high-risk patients and predicts recurrence. Clin Cancer Res. 2014;20(2):344–57.CrossRef Allen MD, Thomas GJ, Clark S, et al. Altered microenvironment promotes progression of preinvasive breast cancer: myoepithelial expression of αvβ6 integrin in DCIS identifies high-risk patients and predicts recurrence. Clin Cancer Res. 2014;20(2):344–57.CrossRef
4.
go back to reference Foroni C, Broggini M, Generali D, Damia G. Epithelial–mesenchymal transition and breast cancer: role, molecular mechanisms and clinical impact. Cancer Treat Rev. 2012;38(6):689–97.CrossRef Foroni C, Broggini M, Generali D, Damia G. Epithelial–mesenchymal transition and breast cancer: role, molecular mechanisms and clinical impact. Cancer Treat Rev. 2012;38(6):689–97.CrossRef
5.
go back to reference Lu W, Kang Y. Epithelial–mesenchymal plasticity in cancer progression and metastasis. Dev Cell. 2019;49(3):361–74.CrossRef Lu W, Kang Y. Epithelial–mesenchymal plasticity in cancer progression and metastasis. Dev Cell. 2019;49(3):361–74.CrossRef
6.
go back to reference Kim YS, Yi BR, Kim NH, Choi KC. Role of the epithelial–mesenchymal transition and its effects on embryonic stem cells. Exp Mol Med. 2014;46:e108.CrossRef Kim YS, Yi BR, Kim NH, Choi KC. Role of the epithelial–mesenchymal transition and its effects on embryonic stem cells. Exp Mol Med. 2014;46:e108.CrossRef
7.
go back to reference Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.CrossRef Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.CrossRef
8.
go back to reference Saitoh M. Epithelial–mesenchymal transition is regulated at post-transcriptional levels by transforming growth factor-beta signaling during tumor progression. Cancer Sci. 2015;106(5):481–8.CrossRef Saitoh M. Epithelial–mesenchymal transition is regulated at post-transcriptional levels by transforming growth factor-beta signaling during tumor progression. Cancer Sci. 2015;106(5):481–8.CrossRef
9.
go back to reference Suriyamurthy S, Baker D, Ten Dijke P, Iyengar PV. Epigenetic reprogramming of TGF-beta signaling in breast cancer. Cancers. 2019;11(5):726.CrossRef Suriyamurthy S, Baker D, Ten Dijke P, Iyengar PV. Epigenetic reprogramming of TGF-beta signaling in breast cancer. Cancers. 2019;11(5):726.CrossRef
10.
go back to reference Knudsen ES, Ertel A, Davicioni E, Kline J, Schwartz GF, Witkiewicz AK. Progression of ductal carcinoma in situ to invasive breast cancer is associated with gene expression programs of EMT and myoepithelia. Breast Cancer Res Treat. 2012;133(3):1009–24.CrossRef Knudsen ES, Ertel A, Davicioni E, Kline J, Schwartz GF, Witkiewicz AK. Progression of ductal carcinoma in situ to invasive breast cancer is associated with gene expression programs of EMT and myoepithelia. Breast Cancer Res Treat. 2012;133(3):1009–24.CrossRef
11.
go back to reference Lo PK, Zhang Y, Yao Y, Wolfson B, Yu J, Han SY, Duru N, Zhou Q. Tumor-associated myoepithelial cells promote the invasive progression of ductal carcinoma in situ through activation of TGFbeta signaling. J Biol Chem. 2017;292(27):11466–84.CrossRef Lo PK, Zhang Y, Yao Y, Wolfson B, Yu J, Han SY, Duru N, Zhou Q. Tumor-associated myoepithelial cells promote the invasive progression of ductal carcinoma in situ through activation of TGFbeta signaling. J Biol Chem. 2017;292(27):11466–84.CrossRef
12.
go back to reference Moumen M, Chiche A, Cagnet S, Petit V, Raymond K, Faraldo MM, Deugnier MA, Glukhova MA. The mammary myoepithelial cell. Int J Dev Biol. 2011;55(7–9):763–71.CrossRef Moumen M, Chiche A, Cagnet S, Petit V, Raymond K, Faraldo MM, Deugnier MA, Glukhova MA. The mammary myoepithelial cell. Int J Dev Biol. 2011;55(7–9):763–71.CrossRef
13.
go back to reference Mao SPH, Park M, Cabrera RM, Christin JR, Karagiannis GS, Oktay MH, Zaiss DMW, Abrams SI, Guo W, Condeelis JS, et al. Loss of amphiregulin reduces myoepithelial cell coverage of mammary ducts and alters breast tumor growth. Breast Cancer Res. 2018;20(1):131.CrossRef Mao SPH, Park M, Cabrera RM, Christin JR, Karagiannis GS, Oktay MH, Zaiss DMW, Abrams SI, Guo W, Condeelis JS, et al. Loss of amphiregulin reduces myoepithelial cell coverage of mammary ducts and alters breast tumor growth. Breast Cancer Res. 2018;20(1):131.CrossRef
14.
go back to reference Pandey PR, Saidou J, Watabe K. Role of myoepithelial cells in breast tumor progression. Front Biosci. 2010;15:226–36.CrossRef Pandey PR, Saidou J, Watabe K. Role of myoepithelial cells in breast tumor progression. Front Biosci. 2010;15:226–36.CrossRef
15.
go back to reference Hilson JB, Schnitt SJ, Collins LC. Phenotypic alterations in ductal carcinoma in situ-associated myoepithelial cells: biologic and diagnostic implications. Am J Surg Pathol. 2009;33(2):227–32.CrossRef Hilson JB, Schnitt SJ, Collins LC. Phenotypic alterations in ductal carcinoma in situ-associated myoepithelial cells: biologic and diagnostic implications. Am J Surg Pathol. 2009;33(2):227–32.CrossRef
16.
go back to reference Rohilla M, Bal A, Singh G, Joshi K. Phenotypic and functional characterization of ductal carcinoma in situ-associated myoepithelial cells. Clin Breast Cancer. 2015;15(5):335–42.CrossRef Rohilla M, Bal A, Singh G, Joshi K. Phenotypic and functional characterization of ductal carcinoma in situ-associated myoepithelial cells. Clin Breast Cancer. 2015;15(5):335–42.CrossRef
17.
go back to reference Xu C, Liu F, Xiang G, et al. β-Catenin nuclear localization positively feeds back on EGF/EGFR-attenuated AJAP1 expression in breast cancer. J Exp Clin Cancer Res. 2019;38(1):238.CrossRef Xu C, Liu F, Xiang G, et al. β-Catenin nuclear localization positively feeds back on EGF/EGFR-attenuated AJAP1 expression in breast cancer. J Exp Clin Cancer Res. 2019;38(1):238.CrossRef
18.
go back to reference Sikandar SS, Kuo AH, Kalisky T, Cai S, Zabala M, Hsieh RW, Lobo NA, Scheeren FA, Sim S, Qian D, et al. Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis. Nat Commun. 2017;8(1):1669.CrossRef Sikandar SS, Kuo AH, Kalisky T, Cai S, Zabala M, Hsieh RW, Lobo NA, Scheeren FA, Sim S, Qian D, et al. Role of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis. Nat Commun. 2017;8(1):1669.CrossRef
19.
go back to reference Logullo AF, Nonogaki S, Pasini FS, Osório CA, Soares FA, Brentani MM. Concomitant expression of epithelial–mesenchymal transition biomarkers in breast ductal carcinoma: association with progression. Oncol Rep. 2010;23(2):313–20.PubMed Logullo AF, Nonogaki S, Pasini FS, Osório CA, Soares FA, Brentani MM. Concomitant expression of epithelial–mesenchymal transition biomarkers in breast ductal carcinoma: association with progression. Oncol Rep. 2010;23(2):313–20.PubMed
20.
go back to reference Choi Y, Lee HJ, Jang MH, Gwak JM, Lee KS, Kim EJ, Kim HJ, Lee HE, Park SY. Epithelial–mesenchymal transition increases during the progression of in situ to invasive basal-like breast cancer. Hum Pathol. 2013;44(11):2581–9.CrossRef Choi Y, Lee HJ, Jang MH, Gwak JM, Lee KS, Kim EJ, Kim HJ, Lee HE, Park SY. Epithelial–mesenchymal transition increases during the progression of in situ to invasive basal-like breast cancer. Hum Pathol. 2013;44(11):2581–9.CrossRef
21.
go back to reference Guarino M. Epithelial–mesenchymal transition and tumour invasion. Int J Biochem Cell Biol. 2007;39(12):2153–60.CrossRef Guarino M. Epithelial–mesenchymal transition and tumour invasion. Int J Biochem Cell Biol. 2007;39(12):2153–60.CrossRef
22.
go back to reference Hu M, Yao J, Cai L, Bachman KE, van den Brule F, Velculescu V, Polyak K. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet. 2005;37(8):899–905.CrossRef Hu M, Yao J, Cai L, Bachman KE, van den Brule F, Velculescu V, Polyak K. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet. 2005;37(8):899–905.CrossRef
23.
go back to reference Werling RW, Hwang H, Yaziji H, Gown AM. Immunohistochemical distinction of invasive from noninvasive breast lesions: a comparative study of p63 versus calponin and smooth muscle myosin heavy chain. Am J Surg Pathol. 2003;27(1):82–90.CrossRef Werling RW, Hwang H, Yaziji H, Gown AM. Immunohistochemical distinction of invasive from noninvasive breast lesions: a comparative study of p63 versus calponin and smooth muscle myosin heavy chain. Am J Surg Pathol. 2003;27(1):82–90.CrossRef
24.
go back to reference Hsiao YH, Su YA, Tsai HD, Mason JT, Chou MC, Man YG. Increased invasiveness and aggressiveness in breast epithelia with cytoplasmic p63 expression. Int J Biol Sci. 2010;6(5):428–42.CrossRef Hsiao YH, Su YA, Tsai HD, Mason JT, Chou MC, Man YG. Increased invasiveness and aggressiveness in breast epithelia with cytoplasmic p63 expression. Int J Biol Sci. 2010;6(5):428–42.CrossRef
25.
go back to reference Russell TD, Jindal S, Agunbiade S, Gao D, Troxell M, Borges VF, Schedin P. Myoepithelial cell differentiation markers in ductal carcinoma in situ progression. Am J Pathol. 2015;185(11):3076–89.CrossRef Russell TD, Jindal S, Agunbiade S, Gao D, Troxell M, Borges VF, Schedin P. Myoepithelial cell differentiation markers in ductal carcinoma in situ progression. Am J Pathol. 2015;185(11):3076–89.CrossRef
26.
go back to reference Wendt MK, Smith JA, Schiemann WP. Transforming growth factor-beta-induced epithelial–mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene. 2010;29(49):6485–98.CrossRef Wendt MK, Smith JA, Schiemann WP. Transforming growth factor-beta-induced epithelial–mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene. 2010;29(49):6485–98.CrossRef
27.
go back to reference Martinez EF, Demasi AP, Napimoga MH, Arana-Chavez VE, Altemani A, de Araujo NS, de Araujo VC. In vitro influence of the extracellular matrix in myoepithelial cells stimulated by malignant conditioned medium. Oral Oncol. 2012;48(2):102–9.CrossRef Martinez EF, Demasi AP, Napimoga MH, Arana-Chavez VE, Altemani A, de Araujo NS, de Araujo VC. In vitro influence of the extracellular matrix in myoepithelial cells stimulated by malignant conditioned medium. Oral Oncol. 2012;48(2):102–9.CrossRef
28.
go back to reference Moirangthem A, Bondhopadhyay B, Mukherjee M, Bandyopadhyay A, Mukherjee N, Konar K, Bhattacharya S, Basu A. Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes. Sci Rep. 2016;6:21903.CrossRef Moirangthem A, Bondhopadhyay B, Mukherjee M, Bandyopadhyay A, Mukherjee N, Konar K, Bhattacharya S, Basu A. Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes. Sci Rep. 2016;6:21903.CrossRef
29.
go back to reference Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6(1):17–32.CrossRef Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, Porter D, Hu M, Chin L, Richardson A, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6(1):17–32.CrossRef
30.
go back to reference Martinez EF, Napimoga MH, Montalli VA, de Araujo NS, de Araujo VC. In vitro cytokine expression in in situ-like areas of malignant neoplasia. Arch Oral Biol. 2013;58(5):552–7.CrossRef Martinez EF, Napimoga MH, Montalli VA, de Araujo NS, de Araujo VC. In vitro cytokine expression in in situ-like areas of malignant neoplasia. Arch Oral Biol. 2013;58(5):552–7.CrossRef
Metadata
Title
TGF-β1 stimulates epithelial–mesenchymal transition and cancer-associated myoepithelial cell during the progression from in situ to invasive breast cancer
Authors
Li Wang
Cong Xu
Xia Liu
Yang Yang
Lu Cao
Guomin Xiang
Fang Liu
Shuling Wang
Jing Liu
Qingxiang Meng
Jiao Jiao
Yun Niu
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-1068-7

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