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Wallace et al. J Cancer Metastasis Treat 2019;5:9 I http://dx.doi.org/10.20517/2394-4722.2019.01 Page 3 of 18

gland is not achieved until pregnancy, where progesterone and prolactin coordinate differentiation of the
alveolar structures that are responsible for milk storage and secretion; in addition, continued branching
morphogenesis occurs to prepare the gland for lactation [23,26] . During lactation, oxytocin stimulates the
[27]
contraction of myoepithelial cells in response to suckling, resulting in milk delivery via the nipple . When
lactation ends, the gland must cease milk production and return to the pre-pregnant architecture through
postpartum involution.

Postpartum involution involves the upregulation of tumor-promotional factors in the mammary epithelium
and surrounding stroma. As primary components of the mammary ECM, collagen proteins, and the
fibroblasts that produce and remodel them, have been extensively studied for their role in breast tumor
progression and metastasis [28,29] . The 28 types of collagen proteins share a triple α-helix as part of their
[30]
structure, and they can be broadly classified as fibrillar or non-fibrillar based on their assembly . For
[30]
additional information on collagen and its assembly, see Mouw et al. . In this review, we will focus on
[31]
fibrillar collagen, as this is the most abundant form in the mammary gland . Collagen I expression is both
spatially and temporally regulated, and its tight control is essential for the proper mechanosignaling required
[31]
for normal mammary gland development and function . In fact, dysregulation of the primary collagen
I receptor, α b integrin, can alter mammary ductal branching and promote tumor formation [32,33] . The
2 1
contribution of collagen to tumor progression is emphasized by the prognostic value of collagen I mRNA
[34]
in clinical outcomes of breast cancer and evidence that increased collagen density promotes local breast
[35]
cancer invasion and distant metastasis . One way that collagen deposition is regulated during involution is
by the pro-inflammatory enzyme COX-2.

COX enzymes were first identified as the targets of inhibition by aspirin and other non-steroidal anti-
[36]
inflammatory drugs (NSAIDs) . COX enzymes exist in two isoforms, both of which bind to cell
membranes where they catalyze the metabolism of free arachidonic acid (AA) to prostaglandins (PGs) via
phospholipase A2 [37,38] . First, COX enzymes rapidly catalyze the formation of an unstable intermediate,
prostaglandin G2 (PGG2), from AA. PGG2 is then rapidly converted to prostaglandin H2 (PGH2) via COX-
mediated peroxidase activity. Finally, specialized prostaglandin synthases result in the conversion of PGH2
to specific, biologically active PGs [37-39] . Though initially believed to function identically, later investigations
[40]
revealed important differences between COX-1 and COX-2 . COX-1 is constitutively expressed as a
[41]
regulator of tissue homeostasis , whereas COX-2 is not normally expressed in adult tissues, with the
[42]
[43]
exception of the central nervous system , kidneys , and male reproductive organs [40,44] . Unlike COX-1,
COX-2 expression is regulated by mitogens, hormones, and cytokines, and it is also correlated with cancer
progression [45,46] . However, it is the product of COX-2 activity - PGE2 - that serves as the active effector of
pro-tumorigenic signaling. Once synthesized, PGE2 can bind to specific E-prostanoid receptors on the cell
[47]
surface to activate pathways associated with survival and inflammation . COX-2/PGE2 signaling has been
described in multiple models of cancer, including oral, breast, prostate, and colorectal, with documented
roles in tumor initiation, invasion, immune evasion, cell survival, metastasis, vascular remodeling, cancer
[46]
[48]
stem cells, and drug resistance; for further review, see Hashemi Goradel et al. and Stasinopoulos et al. .
[18]
In addition to the feedback between COX-2 and collagen deposition in involution and in breast cancer ,
we have also published a connection between COX-2 and tumor cell invasion through expression of the
[49]
neuronal guidance protein, SEMA7A .
[50]
SEMA7A, or CD108w, was first recognized for its expression on lymphocytes ; however, a role for SEMA7A
in cancer was later identified through its association with Plexin-C1, the receptor for the viral homolog of
SEMA7A. Engagement of Plexin C1 by viral semaphorin inhibits dendritic cell adhesion and motility via
[51]
alterations to the actin cytoskeleton . Similarly, in melanoma, SEMA7A/Plexin-C1 engagement inhibits
[52]
cell migration via inactivation of the cofilin pathway . Cofilin activation, which normally generates free
[54]
[53]
actin filaments required for cell migration is considered a major component of the metastatic cascade .
SEMA7A/Plexin-C1 mediated cofilin inactivation led to the identification of Plexin-C1 as a novel tumor