PhDAlterations to the tumour microenvironment is a common feature of many
cancers, including breast cancer, and there is increasing evidence that alterations
to the microenvironment, including; increased integrin expression, ECM
deposition and protease activity, promote cancer progression. Most invasive
breast cancers arise from a preinvasive stage, ductal carcinoma in situ (DCIS).
Previous work in our laboratory has shown the microenvironment of DCIS is
altered, such that myoepithelial cells (MECs) switch to a tumour-promoting
phenotype, associated with upregulation of integrin αvβ6 and fibronectin (FN)
expression. Mechanisms by which integrin αvβ6 and FN expression are regulated
is unclear. We show DCIS progression into invasion is accompanied by an
increase in MEC expression of integrin αvβ6 and periductal FN deposition, and
their expression were associated in DCIS. These findings were modelled in
isolated primary DCIS-MECs, primary normal MECs and MEC lines, with and
without integrin αvβ6 expression, where integrin αvβ6-positive MECs
upregulating FN expression. We identified integrin αvβ6-positive DCIS ducts
were larger than integrin αvβ6-negative DCIS ducts, and mechanical stretching
of primary normal MECs and a normal MEC line led to upregulation of integrin
αvβ6 expression and FN deposition in a TGFβ-dependent manner. We further
show upregulation of integrin αvβ6 and FN by MECs mediate TGFβ-dependent
upregulation of MMP13 which promotes breast cancer cell invasion in vitro.
These data show altered tissue mechanics in DCIS and MEC expression of
integrin αvβ6 and FN deposition are linked, and implicate TGFβ in their activation.
These findings suggest integrin αvβ6 and FN may be used as markers to stratify
DCIS patients