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Allen, Michael D., Thomas, Gareth J., Clark, Sarah, Dawoud, Marwa M., Vallath, Sabarinath, Payne, Sarah J., Gomm, Jennifer J., Dreger, Sally A., Dickinson, Sarah, Edwards, Dylan 
ORCID: https://orcid.org/0000-0002-3292-2064, Pennington, Caroline J., Sestak, Ivana, Cuzick, Jack, Marshall, John F., Hart, Ian R. and Jones, J. Louise
(2014)
Altered microenvironment promotes progression of preinvasive breast cancer: Myoepithelial expression of v 6 integrin in DCIS identifies high-risk patients and predicts recurrence.
Clinical Cancer Research, 20 (2).
pp. 344-357.
ISSN 1078-0432
Abstract
Purpose: This study investigated the functional and clinical significance of integrin αvβ6 upregulation in myoepithelial cells of ductal carcinoma in situ (DCIS). Experimental Design: Archival samples of DCIS and DCIS with associated invasion (n = 532) were analyzed for expression of αvβ6 by immunohistochemistry and ability to predict recurrence and progression assessed in an independent, unique cohort of DCIS cases with long-term follow-up. Primary myoepithelial cells and myoepithelial cell lines, with and without αvβ6 expression, were used to measure the effect of αvβ6 on growth and invasion of tumor cell lines in vitro and in a xenograft mouse model. Involvement of TGFβ signaling was established using mink lung epithelial cell (MLEC) assay and antibody inhibition, and expression and activation of matrix metalloproteinase (MMP)-9 established by Real Time-PCR and zymography. Results: Expression of αvβ6 is significantly associated with progression to invasive cancer (P < 0.006) and with recurrence over a median follow-up of 114 months in a series of matched DCIS cases treated with local excision. We show that expression of αvβ6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor-promoting effect of αvβ6-positive myoepithelial cells is dependent on TGFβ-driven upregulation of MMP9 and can be abrogated by inhibiting this pathway. Conclusion: These findings indicate that altered myoepithelial cells in DCIS predict disease progression and recurrence and show that upregulation of αvβ6 on myoepithelial cells generates a tumor promoter function through TGFβ upregulation of MMP-9. These data suggest that expression of αvβ6 may be used to stratify patients with DCIS.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School Faculty of Science > School of Biological Sciences Faculty of Science |
| UEA Research Groups: | Faculty of Science > Research Groups > Cells and Tissues Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies |
| Depositing User: | Pure Connector |
| Date Deposited: | 26 Mar 2014 13:22 |
| Last Modified: | 31 Oct 2023 01:43 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/48288 |
| DOI: | 10.1158/1078-0432.CCR-13-1504 |
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