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

Sundee Dees,Isabelle Mercier,Laura Pontiggia,Jean-Francois Jasmin,Federica Sotgia,Michael P Lisanti

doi:10.18632/aging.103586

Sundee Dees, Isabelle Mercier + Show 4 more

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https://doi.org/10.18632/aging.103586

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Journal: Aging	Publication Date: Jul 9, 2020
Citations: 3	License type: cc-by

Affiliation: University of the Sciences, University of Salford

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.

Highlights

According to the American Cancer Society, an estimated 250,000 women will be diagnosed with breast cancer (BCa) this year alone and more than 40,000 women will succumb to this devastating disease
We compared branching and lesion formation in ovariectomized female WT, Cav-1 KO, and Cav-1/Signal Transducer and Activator of Transcription 5a (STAT5a) double knockout mice treated with an estrogen regimen for 60 days by performing whole mounts analysis
While mice lacking Cav-1 expression exhibited a significant increase in mammary foci formation following estrogen stimulation compared to WT mice (19.3-fold, p

Summary

Introduction

According to the American Cancer Society, an estimated 250,000 women will be diagnosed with breast cancer (BCa) this year alone and more than 40,000 women will succumb to this devastating disease. DCIS lesions are associated with an increased risk of progressing to invasive breast cancer (IBC) over time [1,2,3,4]. There is increasing attention to a specific role of Cav-1 in the tumor-associated stroma. A loss of Cav-1 expression in the breast tumor stroma correlated with an increased risk for early recurrence, metastatic progression, and decreased survival in patients [11,12,13]. A retrospective patient cohort study revealed that nearly 90% of estrogen receptor (ER) positive DCIS patients that had recurred to IBC showed diminished or completely absent Cav-1 expression in their tumor stroma [14]. Very little is currently known about the underlying mechanisms associated with DCIS formation and progression in the context of a Cav-1 negative micro-environment

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