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Page 2 of 20 Smigiel et al. J Cancer Metastasis Treat 2019;5:47 I http://dx.doi.org/10.20517/2394-4722.2019.26

Keywords: Cell plasticity, pre-malignant plasticity, breast cancer, epithelial-mesenchymal transition/cancer stem
cell, metastasis

INTRODUCTION: THE MORTALITY OF METASTATIC BREAST CANCER
Breast cancer (BC) is the most commonly diagnosed cancer among women, and the second leading cause
of cancer related deaths in women . The statistics highlight the importance of metastasis in BC mortality:
[1]
in patients with distant metastasis, 5-year survival rates are only 22% (13% at 10 years), compared to 90% for
patients with local disease . Furthermore, for those patients with metastatic BC (mBC), there are currently
[2]
no effective treatment options. Understanding how BC cells escape the primary tumor, spread to distant
organs, initiate outgrowth at a distant site, and then developing therapies to target those metastatic processes
remains a significant clinical challenge. Our understanding of the metastatic cascade has increased in recent
years: cells must degrade the extracellular matrix (ECM) surrounding them, extravasate into the circulatory
or lymphatic system and circulate throughout the body, intravasate into the new organ tissue, and regain
their proliferative capacity . Yet, the molecular mechanisms driving each of these processes, all of which
[3-5]
are important for a successful metastatic event, remain unresolved.

A complicating factor to our understanding of BC metastasis is the heterogeneous milieu of the primary
tumor site, or tumor micro-environment (TME), which is comprised of epithelial, endothelial, immune,
and stromal cells. It is important to note that the epithelial populations can be subdivided into two distinct
groups, malignant and pre-malignant. The malignant population has completed the transformation process
through loss of tumor suppressive mechanisms and a gain of oncogenic signaling, via genetic mutation or
sustained growth factor or cytokine signaling. Conversely, pre-malignant refers to a spectrum of points
on the path towards transformation. Pre-malignant cells drift further from normalcy as they acquire
mutations and engage aberrant signaling. If intact, a tumor suppressive response may be engaged to halt the
transformation process, however if lost, the cell may progress to a fully transformed endpoint. The complex
cellular composition within the TME results in a network of secreted factors and ECM proteins, which also
profoundly influence metastatic potential . Numerous TME factors can drive epithelial cells to undergo
[6-9]
epithelial-mesenchymal transition (EMT) and acquire cancer stem cell (CSC) properties, which we refer
to as epithelial-mesenchymal (E-M)/CSC plasticity [10-14] . Seminal work has defined E-M/CSC plasticity as
an important step in metastasis and is often investigated from the perspective of a malignant population.
However, malignant cells are not the only populations capable of undergoing E-M/CSC reprogramming.
Recent evidence has demonstrated a remarkable ability of pre-malignant epithelial cells to take on a more
invasive phenotype able to intravasate and disseminate to secondary sites following signaling cues from the
TME [15,16] . Here, we discuss the challenges of targeting various cell populations and the signaling pathways
that contribute to the cellular plasticity driving mBC. Importantly, we will explore the impact of pre-
malignant cells escaping senescence by undergoing E-M/CSC reprogramming to gain invasive, metastatic,
and tumor-initiating properties. Identifying determinants of metastasis, such as E-M/CSC plasticity, and
advancing our ability to target the drivers of plasticity will have a significant impact on survival for those
with mBC.

SETTING THE STAGE: HETEROGENEITY WITHIN THE PRIMARY SITE
A major challenge in dealing with BC is the heterogeneity that accompanies it. With three distinct clinical
subtypes, estrogen and progesterone receptor positive (ER+/PR+), human epidermal growth factor receptor
2 positive (HER2+), and triple negative breast cancer (TNBC; negative for ER, PR, HER2 expression),
finding the proper treatment options can be difficult [17-19] . Therapies targeting ER/PR hormone signaling via
selective estrogen receptor modulators (SERMs) or aromatase inhibitors (i.e., Tamoxafin and Arimidex) have
significantly improved patient survival and have made this subtype more manageable. Likewise, HER2+