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Page 2 of 18 Wallace et al. J Cancer Metastasis Treat 2019;5:9 I http://dx.doi.org/10.20517/2394-4722.2019.01

Keywords: Postpartum involution, postpartum breast cancer, Semaphorin 7a, cyclooxygenase-2, collagen, metastasis

BREAST CANCER METASTASIS AND POSTPARTUM BREAST CANCER
In the United States, breast cancer remains the second leading cause of cancer related death in women,
with the majority of these deaths resulting from metastatic disease. Breast cancer is a heterogeneous disease
with five identified molecular sub-types: luminal-A, luminal-B, HER2-enriched, basal-like, and normal-
[1]
like . Treatments for hormone receptor positive and HER2 amplified cases include targeted therapies that,
while initially successful, often result in the development of resistance, thereby increasing the likelihood
[2]
of metastasis . Breast cancers lacking estrogen receptor, progesterone receptor, and HER2 amplification
are defined as triple negative breast cancers (TNBC) and account for 15%-20% of breast cancer diagnoses.
Patients with TNBC not only have lower survival rates due to increased early metastasis, but also lack a
[3,4]
targeted therapeutic option . This evidence underscores the necessity of novel models for the identification
of molecular drivers of breast cancer progression, therapy resistance, and metastasis.

Multiple epidemiological studies highlight the effect of pregnancy on breast cancer risk. While first
pregnancy at an early age confers a lifelong protective effect against breast cancer, all women who have given
[5-9]
birth undergo a transient period of increased risk . Previously, women diagnosed within five years of most
recent childbirth were found to be at higher risk for developing metastatic breast cancer than nulliparous
women [5-12] , a risk that persists even after adjustments have been made for variability in hormonal receptor
status, HER2 status, age, histological grade, tumor size, node status, and year of diagnosis [10,13] . More recent
results have revealed that the probability of metastasis is increased for women diagnosed with breast cancer
between 0-5 and 5-10 years postpartum. Thus, we now define breast cancers diagnosed within 10 years
of most recent childbirth as postpartum breast cancer (PPBC) [10,13] . By this definition, PPBC accounts for
over half of all breast cancers diagnosed in women under age 40 in two independent cohorts [10,13] . Since
patients with PPBC have significantly worse outcomes, regardless of numerous clinical parameters, it has
been hypothesized that pro-tumorigenic changes in the breast tissue following pregnancy may persist for
[14]
an extended period and accelerate PPBC progression. Consistent with this hypothesis, Asztalos et al.
identified a breast cancer associated genetic signature in the normal breast tissue of parous women that
persists for up to 10 years after childbirth. Further evidence of a postpartum tumorigenic signature is
supported by multiple pre-clinical models, where implantation of tumor cells into rodent mammary
glands after weaning facilitates tumor cell growth, invasion, and metastasis. Additional studies of the
mammary gland after lactation have revealed that these phenotypes are driven, in part, by mammary and
tumor specific increases in pro-inflammatory cyclooxygenase-2 (COX-2), fibrillar collagen, semaphorin 7a
(SEMA7A), bone marrow derived stromal and macrophage populations, lymphangiogenesis, and circulating
estrogens [15-22] . In this review, we will explore some of the mechanisms by which post-lactational changes in
the mammary gland facilitate breast cancer progression and metastasis, with a focus on the roles of collagen,
COX-2, and SEMA7A in cell death, extracellular matrix (ECM) and vascular remodeling, and macrophage
infiltration.

PRO-TUMORIGENIC ROLES OF INVOLUTION ASSOCIATED PROGRAMS
For a detailed review of the events that occur during embryonic and adult mammary gland development,
[23]
see Macias and Hinck . Briefly, mammary gland development begins during embryogenesis where
[24]
ectodermal placodes invade into the mammary mesenchyme to form a rudimentary ductal tree . This
primitive structure persists until puberty where upregulation of growth hormone and estrogen coordinate
ductal morphogenesis to form the extensive epithelial ductal network that fills the mammary fat pad.
Mammary epithelial structures are bi-layered, meaning they consist of both luminal cells and basally
[25]
restricted myoepithelial cells that contact the basement membrane . Full differentiation of the mammary