Page 650 - Read Online

Page 2 of 14 Tafur et al. J Cancer Metastasis Treat 2018;5:xx I http://dx.doi.org/10.20517/2394-4722.2018.102

transporters; 2, lower levels of intracellular lactate; and 3, decreased proliferation and survival in lactate only-
containing conditions. GPR81 siRNA plus tamoxifen displayed additive suppressive effects on MCT1 expression and
cell viability.

Conclusion: GPR81 promotes the ability of epithelial breast cancer cells to import lactate for energy use. As such,
GPR81 represents a potential target for treatment of hormone-positive breast cancer cells, and may be prognostic
for higher grade breast cancer.

Keywords: GPR81, lactate metabolism, MCT transporters, MCT1, tamoxifen

INTRODUCTION
Invasive breast cancer (IBC) is the most predominant form of cancer among women worldwide and the
second leading cause of cancer-related deaths in women in the United States . Moreover, breast cancer
[1,2]
is a complex and heterogeneous disease, which includes a range of pathological subtypes associated with
different clinical behavior, treatment options and outcomes. The most common subtype of IBC, termed
Luminal A, is characterized by an adhesive epithelial phenotype and defined by the overexpression of the
estrogen receptor α (ERα) that underlies the endocrine-based treatment of this subtype . Although Luminal
[3]
A IBC is a relatively non-aggressive type with a good response to adjuvant endocrine therapy and a high
survival rate, failure of early detection is associated with metastatic disease, which in turn is responsible for
the majority of deaths in breast cancer patients.

The metastatic dissemination of epithelial IBC cells is initiated by the reprogramming of cellular regulatory
pathways that induce a coordinated downregulation of cell-cell adhesion and the acquisition of motility and
invasiveness in a subpopulation of cancer cells. Epithelial-mesenchymal transition (EMT) has been proposed
as a key regulatory program that drives these early metastasis-related changes . The process of EMT can
[4]
be induced by exposure of cancer cells to an altered microenvironment (e.g., hypoxia, pro-inflammatory
cytokines), often in conjunction with somatic mutations .
[5,6]
We previously reported that prolonged mammosphere culture induced EMT in two distinct epithelial breast
cancer cell lines, MCF-7 and BT-474 cells, and generated stable populations of mesenchymal cancer cells,
MCF-7M and BT-474M . EMT promoted a more glycolytic phenotype compared to the parental epithelial
[7,8]
breast cancer cells that primarily use oxidative phosphorylation to produce ATP (submitted manuscript).
The altered metabolic phenotype induced by EMT involved enhanced aerobic glycolysis (i.e., the Warburg
effect) along with higher rates of lactate production and extracellular acidification.

As a result of the glycolytic shift induced by EMT, mesenchymal cells co-export higher amounts of lactate
and protons to the extracellular microenvironment, thereby creating an acidic microenvironment that has
been associated with tumor progression . Elevated levels of lactate within the tumor microenvironment
[9]
have been associated with metastasis and poor prognosis of cancer patients [10-12] . Once exported, lactate can
act both as a carbon source for other cells and as a signaling molecule. For example, lactate produced by
highly glycolytic cancer cells can be utilized by neighboring oxidative cancer cells for ATP production, a
phenomenon known as “metabolic symbiosis” [13,14] . As a “signaling molecule”, lactate can regulate migration,
angiogenesis, immune escape and metastasis [15-17] .

Intracellular and extracellular lactate levels are determined, in part, by different isoforms of the lactate/H+
symporter, termed monocarboxylate transporters (MCTs) [18,19] . MCT isoforms are lactate/proton co-transporters,
and thus contribute to the acidification and lactate accumulation and signaling in the tumor microenvironment .
[20]