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.