Page 135 - Read Online

Wallace et al. J Cancer Metastasis Treat 2019;5:9 I http://dx.doi.org/10.20517/2394-4722.2019.01 Page 7 of 18

Transforming growth factor b (TGFb), well-known for its paradoxical role in breast tumor progression, is
[98]
a primary regulator of collagen deposition in the mammary gland . At approximately 8 h post weaning,
TGFb becomes activated and exerts tumor suppressive effects via activation of apoptotic programming [73,99] .
Conversely, when normal cells begin to take on tumorigenic phenotypes, TGFb promotes cancer progression
by enhancing tumor cell survival and contributing to the maintenance of cancer stem cell populations [100] .
TGFb is also essential for wound healing, where it stimulates ECM deposition via fibroblast activation [101] .
Interestingly, TGFb dependent fibroblast activation during involution may be COX-2 dependent, as NSAID
treatment decreases fibroblast activation in vivo. Furthermore, NSAIDs inhibit fibroblast mediated fibrillar
[15]
collagen deposition during involution and in a model of PPBC . Additionally, TGFb is known to positively
regulate SEMA7A in pulmonary fibrosis, where SEMA7A is critical for ECM deposition via activation of the
PI3K/AKT pathway [102] . Given its role in ECM deposition, SEMA7A expression during the second phase of
[57]
involution suggests it may also play a role in mammary gland tissue remodeling . SEMA7A can affect ECM
remodeling through its ability to recruit fibroblasts and immune cells to fibrotic sites, and it has been further
implicated in fibrosis models in the liver, kidney, and in glial scar formation [103-108] . Contradictory to this
role, when endogenously expressed on fibroblasts, SEMA7A can maintain fibroblast homeostasis and reduce
pro-fibrotic markers [109] , indicating context dependent roles for SEMA7A-mediated signaling. In cancer,
fibrillar collagen coordinates upregulation of COX-2 on tumor cells, further promoting tumor cell invasion
[49]
[7]
and metastasis , and we have published that COX-2 drives SEMA7A expression . Thus, fibrillar collagen,
COX-2, and SEMA7A may be a part of a feed-forward loop that ultimately results in cancer cell invasion
and metastasis. Additional studies, however, are needed to better understand the hierarchy and cross-talk
between these molecules in the context of postpartum involution and breast cancer progression.

Altering fibrillar collagen deposition provides a route for tumor cell migration and invasion, but also changes
the signals received by cells from the surrounding environment. Signals from the ECM are communicated
to cells by integrins. Integrins are heterodimeric (αb) transmembrane receptors with 18 known α and 8
b integrin subunits, resulting in 24 possible heterodimeric integrin receptors [110] . Proper expression and
signaling of integrins is essential for cell survival and adhesion, and integrin dysregulation can promote
cancer via activation of pathways that affect survival, EMT, and migration [28,111-115] . Specifically, improper
integrin signaling and expression can result in the loss of normal epithelial cell polarity and attachment,
in addition to the over-activation of focal adhesion kinase and subsequent downstream signaling pathways
that promote cell survival, migration, invasion, and ultimately metastasis [116] . While some integrin pairs are
highly specific in their substrate recognition, others can recognize a number of substrates from the ECM,
as well as foreign molecules such as snake venom, viral particles, and pathogens [117,118] . Alternative ligand-
binding partners and/or differential integrin expression can elicit different signaling pathways; thus, when
either ligand or integrin profiles are altered, cellular signaling pathways can become aberrantly activated or
inhibited. Abnormal SEMA7A expression during involution and/or cancer may promote tumorigenesis via
activation of b1-integrin and downstream pathways. SEMA7A binds to b1-integrin via the RGD binding site
located on the SEMA domain; however, this site is buried in the crystal structure when SEMA7A is bound to
Plexin C1. The ability to differentially regulate tumor progression could, therefore, be explained by binding
of SEMA7A to its different receptors [119,120] . Further, while SEMA7A binds to α b -integrin on inflammatory
1 1
macrophages [121] , the α-binding partner needed for SEMA7A-mediated breast cancer progression is
unknown. As reviewed above, one consequence of SEMA7A-b1-integrin signaling is fibrillar collagen
deposition. Collagen can also activate integrins and modulate their associated signaling pathways, primarily
through α b integrin, which is often upregulated on cancer cells of epithelial origin [122] . Collagen binding
2 1
to α b integrin on tumor cells promotes cellular invasion, which helps cells navigate through the collagen I
2 1
rich mammary TME and distant metastatic sites, such as the bone [122] . Interestingly, α b integrin has been
2 1
shown to increase COX-2 expression in intestinal epithelial cells [123] , leading to activation of downstream
signaling events associated with tumor promotion. While these results further support a link between
COX-2 and collagen, α b integrin has also been recognized as a metastasis suppressor in breast cancer. The
2 1