Introduction
Cancer and tumorigenesis
A set of illnesses known as cancer involve abnormal cell proliferation
and can infiltrate or spread to other regions of the body. In 2020, 18.1
million new cases of cancer occurred, which were 9.3 million male cases
and 8.8 million female cases (1). Its
etiology is largely related to genetic, immunological, and environmental
factors. Defects in immune responses, cell apoptosis, and DNA repair
functions have fundamental role in its development and progression (2,
3). Oncogenes, as important genes involved in cell cycle regulation and
apoptosis, can undergo genetic or epigenetically driven alterations that
lead to cancer (4, 5). The information required to determine cancer risk
factors is provided by epidemiological studies (figure.1 ).
Random mistakes in DNA replication occur at varying rates in various
organisms are among the risk factors for developing cancer. Ionizing
radiation, carcinogens, bacteria, fungi, or viruses, DNA damage
response, metabolism, xenobiotic, immune system, hormone levels, and
lifestyle elements such as smoking, hormone therapy, dietary
consumption, and physical activity are considered as some environmental
risk factors (6, 7).
The biological reactions to ionizing radiation are influenced by several
factors including the type and energy of the radiation particle, the
dosage rate, the types of DNA damage, the cell type, etc. Ionizing
radiation has the ability to damage nucleic acids, which could lead to
alter the regulation of ordinarily expressed DNA (8, 9).
Some types of cancer have been linked
to infections caused by specific organisms. For instance, stomach cancer
correlated to Helycobacter pylori bacterial infections, gallbladder or
colon cancer to Salmonella, hepatitis C and B to liver cancer, Kaposi
sarcoma to the herpes virus, and cervical cancer to the human
papillomavirus infections (10, 11).
Toll-like receptor pathways (TLR), nuclear factor-kappa β (NF-kβ),
cGAS/STING, Janus kinase/signal transducers and activators of
transcription (JAK-STAT), inflammation, and mitogen-activated protein
kinase (MAPK) have reported as the important factors related to the
occurrence of cancer. Interferon (IFN), Interleukins (ILs), and tumor
necrosis factor (TNF)-like cytokines, chemokines, growth factors such as
transforming growth factor (TGF), and vascular endothelial growth factor
(VEGF) play key roles in cancer development. Some inflammatory
metabolites, such as thromboxane, leukotrienes, prostaglandins, and
specific proresolving mediators (SPM), serve as significant regulators
in the initiation and resolution of inflammation in cancer (12, 13).
Breast cancer
Breast cancer, one of the most
prevalent malignancies and the primary cause of cancer-related death in
women worldwide, disrupts the lives of millions of women (14, 15). For
many years, breast cancer has consistently been ranked among the most
lethal cancers in terms of incidence and mortality (16-18). Similar to
other cancers, it is influenced by a person’s lifestyle, environmental
circumstances, and genetic predisposition. Age and breast density are
two examples of natural characteristics that can increase the risk of
breast cancer. In addition, alterations in circadian rhythm, alcohol
consumption, and tobacco chewing or smoking are associated with the
increased risk of breast cancer (19). These circumstances can result in
cellular stress, the increased production of free radical oxygen
species, and changes in progesterone and estrogen hormones, all of which
enhance tumor aggression (20, 21). Common therapies for breast cancer
include chemotherapy, radiation therapy, and surgery, however these
methods have a poor prognosis and long-term negative effects. Breast
cancer therapy is impeded through metastasis, recurrence, and drug
resistance, like treatment for other cancers (22, 23). Scientists are
focusing on nutraceuticals as an emerging medicine with less side
effects to address the issue with breast cancer treatment. Due to lower
drug-related adverse effects and resistance phenomena, nutraceuticals
can also be used as an adjuvant therapy with currently available
chemotherapeutic medicines (24, 25). Since ancient times, people have
used natural remedies made from various plants or non herbal sources to
treat a variety of ailments, with many encouraging results. The need for
developing various herbal and non herbal drugs with therapeutic
potential is growing as a science and technology advance. As a result,
there is plenty of room for innovative, healthy nutrition substrates. In
2017, it was estimated that the global market for nutraceuticals would
reach 734 billion US dollars by 2026 (26, 27). Therapeutic compounds
known as nutraceuticals have drug-like qualities and are used to treat
serious illnesses like cancer, diabetes, atherosclerosis, neurological
diseases, and hematological disorders. According to study, health food
products contain polyphenols, terpenoids, tannins, alkaloids, and
flavonoids, which have a significant potential to combat these fatal
diseases (25, 28, 29). In this review, specific important and pertinent
breast cancer processes are highlighted, and nutraceuticals are assessed
along with their processes and potential in breast cancer prevention.
Breast cancer pathophysiology
Breast cancer typically starts as ductal hyperplasia and progresses
through benign tumors and even metastatic cancer because of numerous
toxins stimulating it. The effect of stroma and tumor microenvironment,
including macrophages, play a critical role in the onset and progression
of the cancer. Macrophages have the ability to create an immune
system-rejecting and mutagenic milieu that promote angiogenesis and
permits cancerous cells to spread (30). The cancer stem cell and the
stochastic theories are two hypotheses that may help to explain the
development and spread of breast cancer. The stochastic hypothesis
postulates that each tumor subtype is derived from a single cell type,
differentiated progenitor, or stem cell. Any breast cell can get random
mutations over time, and when enough mutations have accumulated, the
cell is eventually become a tumor cell. Based on the cancer stem cell
theory, various tumor subtypes develop via identical progenitor cells or
stem cells. Epigenetic and genetic alterations in precursor cells or
stem cells have fundamental role in determining different tumor features
(31).
Limitations of cancer treatments and anticancer drugs
A growing body of studies has performed to develop novel drug delivery
and targeting methods, enhance drug accumulation and its efficacy, and
minimize the negative side effects of medications during the course of
cancer therapy (32). The most current approaches to cancer treatment
include surgery, radiotherapy, chemotherapy, immunotherapy, cancer
vaccines, photodynamic therapy, stem cell transformation, and/or
combinations of these options. These methods are largely related to
serious side effects, including restricted metastasis, toxicity,
nonspecificity, and reduced bioavailability (33-35). Cancer treatments
are dependent on the type, stage, and site of cancer. Cytotoxic and
cytostatic drugs used in chemotherapy can exert their potential impacts
alone and/or in combination with other forms of cancer therapy.
Alkylating compounds, such as carboplatin, cisphamide, oxaliplatin, and
melphalan, may lead to cardiovascular, gastrointestinal, hematologic,
pulmonary toxicities, diarrhea, sensory neuropathy, and neutropenia
(36-38). These compounds are highly successful in treating numerous
malignancies, but they have serious side effects, are expensive,
complex, toxic, and unfriendly to the environment. Some cells, such as
those located in the gastrointestinal tract, bone marrow, and hair
follicles, develop quickly under usual physiological conditions. The
contemporary anticancer medications also target these rapidly growing
healthy cells. These anticancer drugs can lead to GIT inflammation, hair
loss, immunosuppression, cardiac conditions, reduction in blood
production, and neurological issues (Table 1 ).
It is reported that genetic conditions participate in the development of
drug resistance in the cancer cells. ABCA4 and ABCA12 are
mentioned as drug resistance genes related to breast cancer. Previous
studies have indicated overexpression of these genes in human MCF-7
cells after docetaxel treatment. However, their expressions were
downregulated when the phytochemical curcumin was combined with
docetaxel (39). These observations suggest that cancer treatments need a
combination of current therapeutic approaches. Consequently,
plant-derived compounds and related products may provide the most
effective and safest methods for treating different cancers, based on
the findings of many studies (40) .
Plant-derived anticancer compounds
Newman and Cragg provide a full explanation of the functions of natural
chemicals as medications or a foundation for the creation of new
medications (5). They found that 929 new drugs (antiviral, antifungal,
antiparasitic, antibacterial, antitumor, etc.), approved in the last
forty years, had a natural origin. Approximately 29 of the 240
anticancer medications are purely synthetic, which may be due to natural
compounds’ benefits such as fewer side effects and the capacity to
activate a variety of signaling mechanisms involved in cancer
development. Additionally, during the preceding 10 years, synthetic
compounds with natural pharmacological agents that mimic the actions of
natural chemicals have been approved as anticancer medications (41).
In the realm of oncology, the use of herbal remedies has been
extensively accepted as a supplemental or alternative treatment (42,
43). Numerous new cytotoxic chemicals have been discovered from plants
each year, opening up fresh avenues for the treatment of cancer. The
study of naturally occurring molecular entities which could be helpful
to the pharmaceutical business is a focus for many academics (44). When
substances are found to have anticancer effects in preclinical research,
researchers are often looking for a way to confirm their clinical
efficacy. This review has a specific focus on breast cancer and
describes the research on herbal remedies with considerable and active
anticancer activities as well as the anticancer ingredients discovered
in such herbal treatments.