Investigational New Drugs (2021) 39:871–878

https://doi.org/10.1007/s10637-021-01063-z

REVIEW

Gut microbiota homeostasis restoration may become a novel therapy

for breast cancer
Zhi-Peng Feng 1,2,3 & Hong-Yi Xin 4 & Ze-Wei Zhang 5 & Chen-Guang Liu 2,3 & Zheng Yang 1 & Hua You 6 &
Hong-Wu Xin 1,2,3,7

Received: 12 October 2020 / Accepted: 6 January 2021 / Published online: 17 January 2021
# The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021

Summary
Breast cancer is the most diagnosed cancer in women. It significantly impairs a patient’s physical and mental health. Gut
microbiota comprise the bacteria residing in a host’s gastrointestinal tract. Through studies over the last decade, we now know
that alterations in the composition of the gut microbiome are associated with protection against colonization by pathogens and
other diseases, such as diabetes and cancer. This review focuses on how gut microbiota can affect breast cancer development
through estrogen activity and discusses the types of bacteria that may be involved in the onset and the progression of breast
cancer. We also describe potential therapies to curtail the risk of breast cancer by restoring gut microbiota homeostasis and
reducing systemic estrogen levels. This review will further explore the relationship between intestinal microbes and breast cancer
and propose a method to treat breast cancer by improving intestinal microbes. We aimed at discovering new methods to prevent
or treat BC by changing intestinal microorganisms.

Keywords Breast cancer . Gut microbiota . Homeostasis . Novel therapy

Introduction homeostasis may lead to a variety of diseases, such as inflam-

The intestinal microbiota represents a complex ecosystem,
consisting of trillions of bacteria distributed over hundreds
of species, which has evolved along with its hosts over mil-
lions of years. Normal gut microbiota play an important role in
protecting the host against pathogens, regulating metabolism,
and providing nutrition. Disruption of the gut microbiota
matory bowel disease, metabolic syndromes, infection, and
cancer. The density and diversity of these microbial colonies
within the gut can be altered by diet, antibiotics, diseases, and
other environmental factors [1].
Breast cancer (BC) is a major global health issue,
which represents a serious threat to human health. In fact,
BC is one of the most prevalent cancers among women

Zhi-Peng Feng, Hong-Yi Xin and Ze-Wei Zhang contributed equally to

this work.

* Zheng Yang 3
Department of Biochemistry and Molecular Biology, School of Basic
yangzheng_0809@163.com Medicine, Health Science Center, Yangtze University, 1 Nanhuan
Road, Jingzhou 434023, Hubei, China
* Hua You
Youhua307@163.com 4
Department of Microbiology and Immunology, Immunology
* Hong-Wu Xin Programe, Yong Loo Lin School of Medicine, National University of
hongwu_xin@126.com Singapore, Center for Life Sciences, 28 Medical Drive, #03-09,
Singapore 117456, Singapore
1 5
Department of Infectious disease, Jingzhou Central Hospital, The The Fourth Affiliated Hospital, China Medical University,
Second Clinical Medical College, Yangtze University, No. 60 Shenyang 110000, Liaoning, China
Jingzhong Road, Jingzhou District, Jingzhou 434020, Hubei
6
Province, China Affiliated Cancer Hospital and Institute of Guangzhou Medical
2
University, No.78 Heng-Zhi-Gang Road, Yue Xi District,
Laboratory of Oncology, Center for Molecular Medicine, School of Guangzhou 510095, China
Basic Medicine, Health Science Center, Yangtze University, 1
7
Nanhuan Road, Jingzhou 434023, Hubei, China Lianjiang People’s Hospital, Lianjiang 524400, Guangdong, China
872
and is a major cause of cancer death worldwide [2]. More
than half breast cancer patients are not menopausal at the
time of diagnosis, they are steroid hormone receptor-
positive and have a high recurrence rate. Changes in the
intestinal microecology have progressively become a
common concern, as they can play a distant regulatory
role, through multiple mechanisms, affecting the occur-
rence, the development and metastatic dissemination of
BC. Inflammation and estrogen signals play an important
role in human metabolism, which is believed to be asso-
ciated with BC. In fact, research has shown that increased
exposure to estrogens is associated with an elevated risk
of BC [3, 4]. This review will explore the relationship
between intestinal microbes and breast cancer, and pro-
pose a novel approach to treat breast cancer by exploiting
the impact of intestinal microbiota. We aimed at discov-
ering new methods to prevent or treat BC by changing
intestinal microorganisms.
Intestinal microbiome imbalance promotes
cancers
It has been reported that intestinal microbiome imbalance pro-
motes cancers [5–9]. A recent study published in Science in
2018 provides further evidence that gut microbiota composi-
tion modulates the efficacy of anti-PD-1 and anti-PD-L1 im-
munotherapy in patients with epithelial tumors [5].
Microorganisms drive epithelia transformation by affecting
genomic stability, hindering cell apoptosis and releasing cell
proliferation signals [6, 7]. Many bacteria produce molecules
used to attack foreign DNA, aimed at improving their chance
of survival. These substances mainly include bacterial toxins,
which may cause genetic mutations that lead to cancer in the
host. For example, colibactin toxin encoded by PKS loci is
expressed by B2 Escherichia coli, Bacteroides fragilis toxin
(BFT) is produced by enterotoxigenic fragile bacteroides and
cytolethal distending toxin (CDT) is produced by bacteria.
Both colibactin and CDT can cause double-stranded DNA
damage in mammalian cells [6], while BFT can stimulate a
high level of reactive oxygen species (ROS), thereby damag-
ing the host DNA [7]. Cell death or oncogenic mutations
occur when the level of DNA damage exceeds the host cell’s
ability to repair.
In addition to damaging DNA, some microbes are involved in
host carcinogenic pathways and chemotherapy resistance [8, 9].
Intestinal microorganisms are not necessary for chemotherapy
drugs to penetrate tumor cells and form platinum-DNA chain
complexes; however, reduced platinum-drug-induced inflamma-
tory gene expression levels, reduced DNA damage in tumor
cells, and reduced antitumor effects have been observed in sterile
or antibiotics treated mice, suggesting intestinal microbiome is
necessary for chemotherapy efficacy [9].
Invest New Drugs (2021) 39:871–878
Factors that influence intestinal microbiome
imbalance
In 1971, Hill [10] proposed a hypothesis that the gastrointes-
tinal microbiota could produce a carcinogen from a high-fat
diet, which may increase tumor growth by affecting breast
tissue or reacting with estrogen. Although this hypothesis is
controversial, studies on a potential link between intestinal
microbes and BC have increased as a result. Recently, studies
on the relationship between obesity and BC have also been
growing. They have primarily focused on the idea that obesity
can increase the risk of BC by disrupting intestinal microbial
homeostasis and affecting estrogen production. Adipose tissue
is biologically active and it can release inflammatory cyto-
kines and contribute to estrogen levels. Thus, excessive estro-
gen levels and inflammatory cytokines, such as interleukin
(IL)-1, interleukin (IL-6), and tumor-necrosis factor (TNF),
due to elevated fat mass in overweighted people may contrib-
ute to BC development [11]. In murine models of HER-2
positive BC, obese murine show significantly faster tumor
recurrence, further suggesting a link between the biological
environment characteristic of obesity and increased BC risk
[12].
Obesity and BMI are associated with gastrointestinal mi-
crobiota imbalance, and higher BMI is usually associated with
a poor diversity of intestinal microbiota [13]. Long-term con-
sumption of a high-fat diet leads to the growth of bacteria that
produce β-glucuronidase, which increases free estrogen in the
enterohepatic circulation [10]. It was reported that β-
glucuronidase activity in the fecal bacteria of vegetarians,
who have primarily consumed vegetables for a long period
of time, is significantly lower than that of omnivores [1].
Obesity may also lead to an increase of circulating estrogen
through the peripheral aromatization of androgens and inhibi-
tion of the production of liver hormone-binding proteins. This
results in an increase in free estrogen [14]. The long-term
consumption of a high-fat diet is an important factor for obe-
sity. A high-fat diet and obesity can affect gastrointestinal
microorganisms and lead to increased estrogen levels; there-
fore, they may be a risk factor for BC [13, 15].
Excessive alcohol intake can also lead to intestinal flora
imbalance, thereby increasing the number of intestinal bacte-
ria [16–18]. Alcohol is a risk factor for BC, and long-term
drinking can increase the risk of BC. Since ethanol can affect
the metabolism of gut bacteria, which can be mediated
through the intestinal microbial community, long-term and
increased alcohol consumption leads to increased levels of
estrogen. After BC diagnosis, continued drinking can increase
mortality rate and the risk of recurrence after treatment [1],
indicating that alcohol may be a significant risk factor for BC.
The underlying mechanism of these influencing factors re-
mains to be determined as recent studies have been animal-
based and have included small sample sets (Fig. 1).
Invest New Drugs (2021) 39:871–878
Fig. 1 The influencing factors of
intestinal microbiome imbalance
Intestinal microorganisms affect estrogen
metabolism
The metabolism of estrogen occurs in the liver, where the
metabolites are conjugated and excreted into the gastroin-
testinal lumen within the bile. They are de-conjugated by
β-glucuronidase-producing bacteria in gastrointestinal lu-
men, and then they are reabsorbed as free estrogens
through the enterohepatic circulation to reach breast
[19]. All the genes in the gut flora that metabolize estro-
gen are collectively known as the estrobolome [20].
Bacteria expressing estrobolome genes significantly in-
creases the free estrogen in the enterohepatic circulation.
When its homeostasis is disrupted, the intestinal
microbiome is enriched with bacteria β-glucuronidase,
which can be a risk factor for BC. Some studies suggest
that the gut may act as an estrogen accumulator during the
process of estrogen metabolism, acting locally or remotely
to regulate homeostasis and disease development [21].
Once homeostasis in the intestine is disrupted, intestinal
bacteria and LPS are overproduced, pro-inflammatory cy-
tokine levels rapidly increase, and the damaged integrity
of the intestinal mucosa displace bacteria and trigger in-
flammation [22]. Studies show that bacterial translocation
results in elevated levels of inflammatory cytokines [23].
Fig. 2 Intestinal microbiome
imbalance leads to estrogen
increase. Abbreviations: E
represents estrogen, LPS
represents lipopolysaccharide,
COX2 represents cyclooxygenase
2, and PGE2 represents
prostaglandin E2
873
Breast epithelial cells exposed to the pro-inflammatory
cytokine TNF-alpha increase the production of estrogen
[24]. Various studies suggest that one of the inflammatory
mechanisms associated with BC is the upregulation of
cyclooxygenase 2 (COX 2) and its product prostaglandin
E2 (PGE2). This leads to the increased expression of aro-
matase in adipose tissue and an increased conversion of
androgen precursors to estrogen [3]. Increased bacterial
β-glucuronidase and its subsequent effect on inflamma-
tion reduce the risk of BC caused by increased estrogen
levels (Fig. 2).
Relationship between intestinal bacteria
types and breast cancer
Most studies rely on 16S rRNA gene sequences, indicating
that imbalance of intestinal flora is a risk factor for BC and
intestinal microorganisms may affect the risk of BC through
estrogen (Table 1). With the increase of some bacterial types
in the intestinal tract and the decrease of other bacteria, the
diversity of intestinal microbioma is significantly affected and
may be related to the catabolism of intestinal microorganisms.
This may affect estrogen release in the enterohepatic circula-
tion, resulting in increased systemic estrogen levels. Certain
874 Invest New Drugs (2021) 39:871–878

Table 1 Study on the relationship between intestinal flora and breast cancer

Reference Species Methods Related intestinal microorganism Conclusion

Fuhrman [4] Human Pyrosequencing of 16S Order Clostridiales, family Gut microbiota is the modulation of systemic
rRNA amplicons Ruminococcaceae, genus Ruminococcus, estrogens.
genus Bacteroides.
Goedert [25] Human Illumina sequencing and Clostridiaceae, Faecalibacterium, Postmenopausal women with BC have altered
taxonomy of 16S rRNA Ruminococcaceae, Dorea and composition of their gut microbiota.
Lachnospiraceae.
Flores [26] Human Pyrosequencing 16S rRNA Fecal Clostridia taxa, including The gut microbial community likely affects
amplicons non-Clostridiales and three genera in the the risk for estrogen-related conditions in
Ruminococcaceae family. older adults.
Bard [27] Human PCR targeting 16S rRNA Faecalibacterium prausnitzii, Firmicutes, Gut microbiota composition was remarkably
gene sequences Blautia, Bifidobacterium, Prausnitziiand different in differ clinical characteristics
Egerthella. and BMI.
Luu [28] Human Real-time (qPCR) Firmicutes, Faecalibacterium prausnitzii, Gut microbiota composition differs according
and Blautia. to clinical characteristics and BMI.
Shi Jiajie [29] Human Illumina sequencing and Mycobacterium, Rhodococcus, The diversity of the gut microbiota was
taxonomy of 16S Catenibacterium, Bulleidia, Anaerofilum, associated with the expression of TILs in
ribosomal RNA Sneathia, Devosia, Methanosphaera and patients with breast cancer.
Anaerobiospirillum.

bacteria are overexpressed in the intestinal microbiota of BC,
which may have the potential to metabolize estrogen [4]. A
case-control study investigating the correlation between fecal
microbiota and BC in postmenopausal women showed that
the diversity of fecal microbiota in BC patients was changed,
and especially enriched in Clostridiaceae, Faecalibacterium,
Ruminococcaceae, Dorea and Lachnospiraceae [25]. Some
studies have shown that the intestinal microorganisms of BC
patients at different disease stages are also different, and in-
testinal microorganisms are also significant for the prognosis
of BC. Flores reported that the gut microbial community like-
ly affects the risk for estrogen-related conditions in older
adults [26]. Order Clostridiales, family Ruminococcaceae, genus
Ruminococcus, genus Bacteroides can affect systemic estrogens
[4]. Gut microbiota composition was remarkably different in
differ clinical stages and BMI, for Faecalibacterium prausnitzii,
Firmicutes, Blautia, Bifidobacterium, Prausnitziiand Egerthella
[27]. Firmicutes, Faecalibacterium prausnitzii, and Blautia in
breast cancer patients differs according to BMI [28]. Recent
studies have shown that intestinal microorganisms influence the
expression of breast tumor-infiltrating lymphocytes [29]. With
further research, we will be able to assess the effectiveness of
breast cancer treatment by identifying gut microbes. Whether
intestinal microorganisms influence the recurrence and metasta-
sis of BC requires further basic and clinical study.
New proposals for breast cancer therapy
COX-2 inhibitors
At present, some studies indicate that an intestinal microbial
imbalance can increase the risk of BC due to inflammation-
related mechanisms. Currently, COX2 overexpression is re-
puted a significant factor in BC development, and the expres-
sion of COX2 increases with the formation of metastases. In
fact, COX2 is associated with angiogenesis in cancer tissues,
decreased apoptosis of abnormal cells, and tumor metastasis
in BC [30]. COX-2 is produced during inflammation and its
overexpression leads to increased production of prostaglan-
dins. Abnormal COX-2 expression in BC may be related to
the treatment response, prognosis, and recurrence of BC. The
main role of COX-2 is the upregulation of vascular endothelial
growth factor and lymph angiogenesis. This suggests that in
BC patients COX-2 is conducive to the formation of a
neovasculature with greater permeability and the formation
of lymphatic vessels, thus facilitating the metastatic dissemi-
nation [31]. PGE2 derived from COX-2 stimulates the cAMP
(cAMP) → PKA signal transduction pathway, induces the
transcription of CYP19, and leads to increased aromatase ex-
pression, which is conducive to further production of estrogen
[32]. Cancer cells do not undergo normal apoptosis and rather
proliferate indefinitely. Inflammation, COX-2 overexpres-
sion, and PGE2 elevation are anti-apoptotic, while anti-
inflammatory compounds that inhibit COX-2 are pro-apopto-
tic. COX-2 overexpression and prostaglandin biosynthesis in-
hibit BAX, thus preventing cell apoptosis [30]. The expres-
sion of COX2 is correlated with that of interleukin-6, a cyto-
kine that promotes tumor development by regulating multiple
mitogen-activated kinase-dependent signaling pathways
(MAPK) [33]. The SLC2A3 gene, which is also known as
GLUT3, encodes a protein that promotes the transport of glu-
cose across the cell membrane of cancer cells. This specific
glucose transporter is responsible for meeting the energy
needs of cancer cells and is also associated with COX-2
[34]. The use of nonsteroidal anti-inflammatory drugs has also
Invest New Drugs (2021) 39:871–878 875

been associated with lower estrogen levels in the body [35].
Studies have shown that COX-2 inhibitors limit angiogenesis
and prevent the progression and metastasis of animal tumors
[36]. COX-2 overexpression is associated with resistance to
radiotherapy and adverse reactions to chemotherapy drugs,
suggesting that COX-2 inhibitors may exert a therapeutic ef-
fect on COX-2-positive BC patients [37] (Table 2 and Fig. 3).
studies on the mechanism through which intestinal micro-
organisms influence BC. Although improving intestinal
flora may theoretically influence BC development, more
experiments are needed to establish a role for intestinal
microecology on the prevention and treatment of BC.

Outlooks and future perspectives

Intestinal microbiota homeostasis restoration
The imbalance of intestinal microorganisms will indirect-
ly cause an increase of estrogen levels in the body, and
increased risk for BC. Therefore, the reconstruction of
normal intestinal microecology may play a role in the
prevention, treatment, and prognosis of BC. Fecal micro-
biota transplantation is currently the main method of in-
testinal microbial therapy. The introduction of probiotics
is another method to improve the balance of the intestinal
microecological environment. In overweight breast cancer
patients, the treatment with probiotics can significantly
change the species and diversity of intestinal flora, espe-
cially Bacteroidetes and Firmicutes [38]. As a clinical
application for regulating gastrointestinal function, it pro-
motes the growth of beneficial bacteria and inhibits the
growth of harmful bacteria to improve processes in the
gut barrier, including absorption dynamics and immunity.
Fecal bacteria transplantation involves injecting a fecal
bacteria suspension from a healthy person into the diges-
tive tract of a patient, in order to treat the disease by
reconstructing a normal intestinal microecology.
Currently, fecal bacteria transplantation has been effective
in preventing the recurrence of Clostridium difficile infec-
tion, with better results compared with the use of the
antibiotic vancomycin [39]. There have been some basic
BC is a highly prevalent disease in women. Research on
the relationship between intestinal microorganisms and
BC will have an impact on its prevention and treatment
and provide a foundation for the discovery of new treat-
ment methods. Moreover, selective COX-2 inhibitors,
which reduce the systemic inflammatory response, may
have some effect on estrogen levels. A small number of
studies have reported an effect of selective COX-2 inhib-
itors on the prevention and treatment of BC. However,
further large-sample, multicenter studies are needed to
optimize drug dosage and evaluate its therapeutic effects.
More studies are needed to understand the mechanism of
action of selective COX-2 inhibitors in the prevention and
treatment of BC. Although fecal bacteria transplantation
technology has been progressively improved for therapeu-
tic application, there are also hidden dangers of cross-
infection with fecal bacteria transplantation. Therefore,
strict criteria for screening fecal bacteria donors and prop-
er storage standards should be adopted to ensure the safe-
ty and efficacy of fecal bacteria transplantation.
Currently, more studies have been carried out on the local
effects of intestinal microorganisms. The microecology of the
intestinal tract is worth of further study. Basic and clinical
studies on diseases of the digestive system are also being done
incrementally. The tumor microenvironment plays a very

Table 2 COX-2 inhibitors were suggested as a new therapy for breast cancer

Drug Species Efficacy Conclusion Ref.

Celecoxib Human Risk was reduced by 71%. Regular use of cox-2 inhibitors can prevent [31]
the development of BC.
COX-2 inhibitors Human Regular use of cox-2 inhibitors reduced the Regular use of COX-2 inhibitors might re- [32]
risk of BC by 61%–71%. duce BC risk.
Celecoxib Mouse Protein expression of ERα, COX-2, Cyclin A, Celecoxib is important in the prevention and [30]
and Bcl-xL were reduced in treatment of BC.
celecoxib-treated tumor samples.
Selective COX-2 Human The useful of the selective COX-2 inhibitors The selective COX-2 inhibitors play an im- [33]
inhibitors was linked with a reduced rate of BC re- portant role in reducing rate of BC recur-
currence. rence.
Calcitriol and Cell The proliferation of MCF-7 and The combination of calcitriol and celecoxib [34]
celecoxib MDA-MB-231 was inhibited by both showed a cooperative growth-inhibiting
calcitriol and the COX-2 inhibitor effect in BC cell.
celecoxib.
876
Fig. 3 Role of COX-2 in breast
cancer
important role in the process of tumor development [40].
Whether or not intestinal microorganisms contribute to the
local microenvironment of breast tissue may be of interest
for future study.
Acknowledgements We appreciated Luca Tamagnone at Università
Cattolica del Sacro Cuore (Rome, Italy) for his advice and support.
Authors’ contributions Authors contributed to this paper with the design
(ZPF, ZY and HWX), literature search (ZPF and CGL), drafting (ZPF),
revision (ZPF, HYX, ZWZ, CGL, ZY, HY and HWX), editing (ZPF,
HYX, ZWZ, CGL, ZY, HY and HWX) and final approval (ZY, HY
and HWX).
Funding This study was funded by National Natural Science Foundation
of China (81872412); This study was funded by the Innovation Fund
Designated for Graduate Students of Yangtze University Health Science
Center (2020007).
Data availability We declare that data supporting article results reported
in the article is in the published articles.
Compliance with ethical standards
Conflict of interest Author Zhi-Peng Feng declares that he has no con-
flict of interest. Author Hong-Yi Xin declares that he has no conflict of
interest. Author Ze-Wei Zhang declares that he has no conflict of interest.
Author Chen-Guang Liu declares that he has no conflict of interest.
Author Zheng Yang declares that he has no conflict of interest. Author
Zheng-Yang declares that he has no conflict of interest. Author Hua You
declares that he has no conflict of interest. Author Hong-Wu Xin declares
that he has no conflict of interest.
Invest New Drugs (2021) 39:871–878
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Consent for publication We declare that all authors agreed to publish
the manuscript at this journal based on the signed Copyright Transfer
Agreement and followed publication ethics.
Code availability Not applicable.
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