PhD ThesisBackground: The epithelial cells in Ductal Carcinoma in-situ (DCIS) are as
genetically advanced as those in invasive disease therefore attention has
focused on the tumour microenvironment (ME). A key component of the ME
in DCIS is the myoepithelial cell (MEC) lying at the interface of the epithelial
and stromal compartments. MEC are altered in DCIS with loss of Galectin-7
and upregulation of avb6. Galectin-7 is proposed to play a role in control of
apoptosis and adhesion. The hypothesis of this study is that changes in MEC
phenotype in DCIS leads to an altered ME that promotes tumour progression.
Methods: Galectin-7 expression was assessed using immunohistochemistry
in a series of pure DCIS samples (low risk model) and DCIS with co-existent
invasion (high risk model).
An in-vitro model of normal primary myoepithelial cells was used to investigate
the functional impact of loss of Galectin-7. The effect of Galectin-7 loss on
MEC apoptosis, adhesion and migration was investigated. The global impact
of loss of MEC Galectin-7 was explored using RNA sequencing.
Results: There was greater loss of Galectin-7 in DCIS with co-existent
invasion compared to the pure DCIS cohort, whilst the inverse was shown for
avb6. Functional assays demonstrated knockdown of Galectin-7 sensitised
MECs to apoptosis. They were less adhesive and more migratory to laminin
and more adhesive and less migratory to Collagen I.
RNA sequencing shows that silencing Galectin-7 increased LOX expression -
a key regulator of the collagen matrix of the microenvironment.
Conclusion: This study shows that loss of MEC Galectin-7 is associated with
DCIS progression. Loss predisposes MEC to apoptosis and switches
adhesion from basement membrane to interstitial matrix, all of which
destabilizes this key interface in DCIS. Galectin-7 has the potential to be used
in a risk stratification tool for DCIS
