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Page 6 of 18 Wallace et al. J Cancer Metastasis Treat 2019;5:9 I http://dx.doi.org/10.20517/2394-4722.2019.01

have revealed a feed-forward mechanism by which fibrillar collagen deposition during involution requires
[18]
COX-2 expression. COX-2 further promotes increased fibrillar collagen , which is directly associated with
tumor progression and poor prognosis in breast cancer patients [31,84] . Cooperation between fibrillar collagen
and COX-2 may therefore contribute to the pro-tumorigenic nature of the involuting mammary gland.
Similar to postpartum involution, wound healing is a biological process where cell death is accompanied by
collagen remodeling. In the “phoenix rising” model of cell death, discovered in a model of wound healing
and further characterized in cancer, dying cells send signals to stem and progenitor cells to increase their
proliferation, thereby coordinating cell growth with death [85,86] . In dying cells, activation of caspases 3 and 7
results in the release of calcium-independent phospholipase-2, which increases the production and release of
AA from cell membranes. Ultimately, COX-2 and PGE2 synthase convert free AA to PGE2, which increases
[85]
stem and progenitor cell proliferation to promote tissue regeneration . Though the phoenix rising model,
to our knowledge, remains uninvestigated during mammary involution, there are numerous similarities
between the wound healing program and postpartum involution, including apoptosis, clearance of damaged
and dead cells, and activation of similar inflammatory programs. This suggests that this mechanism of
coordinated cell death and tissue regeneration may be conserved in mammary development. Additionally,
these mechanisms seem to be particularly important for the growth and survival of stem and progenitor
cells in response to apoptotic stimuli, thus representing a mechanism of tumor recurrence in response to
chemotherapy. The preceding data may help to further explain the role of collagen, COX-2, and SEMA7A in
facilitating tumor progression following lactation.

EXTRACELLULAR MATRIX AND REMODELING DURING POSTPARTUM INVOLUTION AND

CANCER
In their updated review of the hallmarks of cancer, Hanahan and Weinberg described the tumor
microenvironment (TME) as a critical mediator of cancer progression due to its ability to supply cancer
[87]
cells with signals that promote inflammation, induce angiogenesis, and confer resistance to cell death .
The TME consists of all the cells, ECM molecules, vasculature, and proteins that surround a tumor. The
cross-talk between these components and the tumor can affect tumor growth, survival, metabolism,
metastasis, response to treatment, and recurrence. The contributions of the TME to cancer progression are
[88]
comprehensively reviewed in a recent special issue of Nature Reviews Cancer . In this section, we will
briefly discuss some of the similarities between the tissue microenvironment of the involuting mammary
gland and the TME.

ECM fragments, which can be used as diagnostic markers of disease, are known contributors to cancer for
their ability to participate in cell signaling events and modulate gene expression [31,89] . An investigation of
the tumor-promotional aspects of involution revealed that tumor cells co-cultured with ECM isolated from
involuting rat mammary gland promoted tumor cell invasion, whereas tumor cells co-cultured with ECM
[90]
isolated from nulliparous rat mammary glands did not , suggesting that involution-derived ECM promotes
tumor cell invasion and metastasis. In further support, orthotopic injection of breast cancer cells mixed
with ECM isolated from the mammary glands of rats undergoing postpartum involution also confirmed
[90]
that involution derived ECM promotes metastasis . Additional investigations have confirmed that the
involution microenvironment mirrors the typical breast TME based on their shared availability of ECM
fragments, dramatic increases in fibrillar collagen, and increased MMP activity [90-92] . Specifically, studies
of stomelysin-1 (MMP3), the primary active MMP during the tissue remodeling phase of involution, have
[93]
characterized it as a potent mediator of EMT and other early oncogenic events in the mammary gland .
Furthermore, elevation of fibrillar collagen results in increased collagen crosslinking and ECM stiffening
- characteristics known to accompany breast tumor progression [89,94-96] . Increased collagen deposition and
cross-linking further promote tumor cell invasion and metastasis by providing a structural network for
[97]
tumor cell migration .