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Research Paper|Volume 12, Issue 14|pp 15104—15120

Essential role of STAT5a in DCIS formation and invasion following estrogen treatment

Sundee Dees1, Laura Pontiggia2, Jean-Francois Jasmin1, Federica Sotgia3, Michael P. Lisanti3, Isabelle Mercier1,4
  • 1Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA
  • 2Department of Mathematics, Physics and Statistics, Misher College of Arts and Sciences, University of the Sciences, Philadelphia, PA, USA
  • 3Translational Medicine, School of Science, Engineering and Environment (SEE), Biomedical Research Centre (BRC), University of Salford, Greater Manchester, United Kingdom
  • 4Program in Personalized Medicine and Targeted Therapeutics, University of the Sciences, Philadelphia, PA, USA
Received: November 6, 2019Accepted: June 10, 2020Published: July 9, 2020
https://doi.org/10.18632/aging.103586

Copyright: © 2020 Dees et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Ductal carcinoma in situ (DCIS) is one of the earliest stages of breast cancer (BCa). The mechanisms by which DCIS lesions progress to an invasive state while others remain indolent are yet to be fully characterized and both diagnosis and treatment of this pre-invasive disease could benefit from better understanding the pathways involved. While a decreased expression of Caveolin-1 (Cav-1) in the tumor microenvironment of patients with DCIS breast cancer was linked to progression to invasive breast cancer (IBC), the downstream effector(s) contributing to this process remain elusive. The current report shows elevated expression of Signal Transducer and Activator of Transcription 5a (STAT5a) within the DCIS-like lesions in Cav-1 KO mice following estrogen treatment and inhibition of STAT5a expression prevented the formation of these mammary lesions. In addition, STAT5a overexpression in a human DCIS cell line (MCF10DCIS.com) promoted their invasion, a process accelerated by estrogen treatment and associated with increased levels of the matrix metalloproteinase-9 (MMP-9) precursor. In sum, our results demonstrate a novel regulatory axis (Cav-1♦STAT5a♦MMP-9) in DCIS that is fully activated by the presence of estrogen. Our sudies suggest to further study phosphorylated STAT5a (Y694) as a potential biomarker to guide and predict outcome of DCIS patient population.