Breast Cancer: Current Trends in Molecular Research

Breast cancer is a common death-related cancer in women globally. Early and non-metastatic stage breast cancers are curable in 70-80% of the patients, while advanced-stage distant organ metastatic breast cancers are incurable with present treatment options. Although multiple risk factors are associated with breast cancer, among them, genetic predispositions in BRCA1 and BRCA2 genes are the most causative factor for breast cancer malignancy. The initiation and progression of breast cancer is a multi-step process, which can initiate either in ducts or lobules of the breast tissues. As time progresses pre-invasive lesions form of breast neoplasm transforms into atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS), and eventually become invasive carcinoma. The molecular mechanisms behind the initiation and progression of breast cancer are not completely understood. However, epithelial-mesenchymal transition (EMT) is the assurance of malignancy which disrupts endothelial integrity and therefore, it increases the spreading of cancer cells and facilitates metastasis. After the epithelial-mesenchymal transition of tumor cells, tumor cells invade and migrate the neighboring as well as distant tissues, cross the endothelial barrier and enter the blood, and attach to a secondary site, forming metastases. In this chapter, we have reviewed an overview of the molecular mechanisms of breast cancer progression.

Cancer is the consequence of the recalcitrant multiplication of the transformed cells. Cancer cells grow and proliferate at a fast pace and do not follow normal regulation of cell division. Breast cancer is a heterogeneous group of diseases, which is the second leading cause of death among women. Although androgen is primarily considered a male steroid hormone, it also has an important role in the female reproductive system. The literature evidence suggests the role of androgen receptors (AR) in the normal development of the breast. At puberty, the expression of AR is even more than ER, suggesting its importance during the process of sexual development; its activity maintains the ER-induced cell proliferation and normal development of the breast. Epidemiological studies have suggested a positive correlation between high endogenous androgens and the risk of breast cancer in both pre- and postmenopausal women. In both ER and PR-positive breast cancers, AR is expressed in 60-70% of the cases. AR is also reported to be co-expressed with ER in around 80-90% of breast cancer cases and is considered an independent prognostic factor of ER-positive breast cancers. Tumor-microenvironment has a complex role in tumor initiation, progression, and metastasis. Tumor-infiltrating and resident cells secretes a variety of inflammatory and anti-inflammatory cytokines, which in turn either inhibit or promote tumor growth. Immunosuppressive and immuno-inductive effects of androgen have been reported in various studies. Androgens have been reported to influence the adaptive immune system more than the innate immune system in many ways. Crosstalk of androgen and cytokine signaling has many effects in breast cancer epidemiology. So, in this chapter, we will discuss the various immune-endocrine perspectives of breast cancers. 

 Breast cancer is responsible for cancer-related death among women globally. The known causes of breast cancer include genetic predisposition, dysregulated hormonal signaling due to psychological stress, and aging and lifestyle factors, such as smoking and alcohol consumption. Due to improved treatment strategies, the overall survival is significantly increased; however, it is still significantly associated with death worldwide. Breast cancer's initiation and progression are strongly influenced by genomic instability. Defect in DNA damage response (DDR) pathways, which enable cells to survive, help in the accumulation of mutation, clonal selection, and expansion of cancer cells. Germline mutation in breast cancer susceptibility genes, BRCA1 and BRCA2, TP53, and PTEN, increases the risk of early onset of disease. During the initial and clonal selection of cancer cells, a defect in one DNA repair pathway could potentially be compensated by another pathway. Therefore, cancer cells with defective DNA repair pathways could be easily killed by targeting the compensatory pathways by inducing synthetic lethality. Evidently, cancer cells with defective DDR or decreased DNA repair capacity show synthetic lethality in monotherapy when the backup DNA repair pathway is inhibited. For instance, tumors with defective homologous recombination (HR) can be targeted by inhibitors of double-strand break repair enzymes. Here, we briefly addressed the relevant factors associated with the development of breast cancer and the role of the DDR factor in the development of breast cancer. In addition, recent treatment strategies targeting genomic instability in breast cancer will be summarized as well as how the genomic instability and defective DDR can be targeted for the treatment of breast cancer. 

Applications of bioinformatic methods and high-throughput sequencing techniques have increased exponentially over the last decade, transforming the way we understand complex malignancies such as breast cancer. In this chapter, an overview of recent advances in molecular research in breast cancer using emerging bioinformatics methods is presented. Learnings from scientific studies that have successfully integrated and interpreted massive amounts of data generated from various platforms (multi-omics data) using bioinformatics approaches are also outlined. Additionally, pan-cancer studies that help identify the differences and commonalities across multiple cancers are reviewed. We also discuss bioinformatics applications that transform the way we decipher the OncoGenomic landscape of breast cancer. Finally, this study also summarizes current publicly available bioinformatics tools and databases for breast cancer research. 

Nitric oxide (NO) is a universal, water-soluble, free radical gas, which plays an important role in the physiological along with pathological processes. NO has been shown in the literature as a key player in carcinogenesis as well as tumor development. Still, there is a lot of debate and misunderstanding about its involvement in cancer. It is believed to have both tumoricidal as well as tumor-promoting effects, which are determined by its timing, location, and concentration. NO has been linked to angiogenesis, apoptosis, cell cycle, invasion, and metastasis. On the other hand, it is emerging as a possible anti-oncogenic agent. Strategies for manipulating in vivo production and exogenous delivery of this molecule for therapeutic gain are being investigated. For therapeutic advantage, strategies for controlling in vivo synthesis and exogenous distribution of this molecule are being investigated. Further research in experimental settings and clinical trials is required to enhance innovative NO-based cancer prevention and treatment strategies. The spectrum of NO actions in cancer and the mechanisms by which NO acts in breast cancer are addressed in this article.

Breast cancer (BC) is one of the most diagnosed and worldwide malignancies in females with an estimated 1,300,000 new cases and 465,000 deaths annually. Therefore, early diagnosis and effective treatments of BC are urgently needed in the struggle against this disease. Molecular markers research has gained huge momentum in BC management. Very few molecular markers are in clinical use for BC management. However, owing to BC heterogeneity, more molecular markers are required for better diagnosis and treatment. Humoral immune response defines the generation of autoantibodies (AAbs) in blood against tumor-associated antigens (TAAs). Such AAbs have been showing great promises for biomarker development for cancer detection. Therefore, these candidate AAbs might be useful for developing blood-based detection assays along with other existing diagnostic tools for BC patients. Besides that, AAbs can also assist in the identification of novel TAAs that can further enhance the utility of immuno-proteomics for biomarkers development and targeted therapy. In this scenario, proteomics tools are being extensively utilized to identify novel TAAs. 

 Breast cancer is a very heterogeneous disease at clinical, histological, and molecular levels. It is the leading cause of cancer-related deaths among women. Breast cancer is manageable if diagnosed early at a localized stage, but late diagnosis of metastatic disease has a very low patient survival rate. Further, limited treatment options, insufficient prognostic and diagnostic markers, misdiagnosis and drug resistance pose a greater problem for patient survival and clinical outcome. Consequently, there is a great need to explore newer and more effective diagnostic, prognostic and therapeutic options for managing breast cancer. It is now a well-known fact that along with genetic changes, epigenetic modifications play an important role in the origin and pathogenesis of breast cancer. Universal involvement of epigenetic modifications in breast cancer development makes them useful for diagnosis, prognosis, and follow-up purposes. Further, the reversibility of epigenetic changes makes them attractive targets for breast cancer therapy. Therefore, in this chapter, we will discuss current knowledge on epigenetic involvement in the development of breast cancer and epi drugs as treatment options for breast cancer management.

With the rapid advancement, nanoparticles (NPs) based drug delivery systems have been recognized as expedient over traditional therapeutics for breast cancer, fostering targeted drug release, long circulation time, reduced toxicity, and greater bioavailability. Under normal circumstances when this exogenous structure of nano-scale dimension approaches nearby cells, it evokes early tripping leading to membrane wrapping and NPs cellular uptake. Tailoring NPs structure for safe and intended entry into cells is at the core of nano-therapeutics for attaining high-yield prognostic and therapeutic efficacy. Interestingly NPs uptake is crucial as it unravels pathway selection and is decisive for the intracellular fate of nano-medicine. Over the past, it remained a major challenge to target specifically to improve their delivery. A significant effort has been devoted to understanding the endocytosis of nano-medicine for efficient intracellular delivery of NPs. Here we present an overview of the different endocytic pathways used by cells. Novel strategies in NPs design to exploit the uptake mechanisms to decipher intended uptake and target breast cancer. Current advances and strategies are deployed to breach these barriers and attain the ultimate vision of nano-carriers in diagnostics and therapeutics.

Despite clinical and pharmacological advancement in medical science breast cancer has become a global concern due to the high mortality rate. Breast cancer is mainly associated with altered redox status, cell cycle, chronic inflammation, and increased proliferative rate. Breast cancer has various molecular subtypes and adequate knowledge of these altered cell cycle regulatory cascades and molecular subtypes of breast cancer is a must for proper prognosis and its successful treatment. The discovery of drugs with anticancer properties, particularly against the specific subtype of breast cancer has become a challenging task for cancer researchers. Dietary polyphenolic compounds as cancer chemopreventive agents have drawn much attention among researchers because polyphenolic compounds are natural in origin with lesser side effects and have a wide range of action against various subtypes of breast cancer. Dietary compounds with antioxidant properties have been reported to act on an array of genes and proteins associated with breast cancer pathogenesis and thus regulate the signaling cascade related to autophagy, chronic inflammation, apoptosis, and cell cycle regulation. All in all, these natural compounds regulate growth and progression of a tumour with less or no side effects. Thus, the current article focuses primarily here on various aspects of breast cancer and food polyphenolic compounds as wellas their molecular mechanism for managing breast cancer.

Radiotherapy therapy is one of the effective and curative methods for the treatment of cancer. One of the reasons for the growing popularity and increased outcome of radiotherapy is attributed to the tremendously enhanced capacity of detection and imaging quality with the reduced radiation dose. Breast cancer is the leading cause with the highest percentage incidence in women worldwide and is the leading cause of cancer death, especially in the developing world. Over 50% of breast cancer patients have been prescribed radiotherapy during their cancer disease management. The present chapter discusses a comprehensive approach to the role of radiotherapy in breast cancer, including the theory, different phases, and types, clinical aspects as well as the challenges involved in its optimal outcome. Chemotherapy, hormone therapy, etc., are the primary treatment modalities for breast cancer, outside of surgery. In this chapter, external beam radiation treatment is mainly discussed.

Breast cancer is the most common type of cancer among females worldwide. It is a heterogeneous disease where the treatment strategies depend on several factors, such as tumor stage, menopausal status, breast cancer oncogenes (BRCA1 or BRCA2), and hormone receptor (ER, PR, and HER2) status. Treatment of breast cancer may be neoadjuvant therapy when given before surgery or adjuvant therapy when given after surgery. Adjuvant therapy is also known as systemic therapy, where the cancer cells are treated with chemotherapy, radiotherapy, hormonal therapy, and immunotherapy. In this article, we present current therapeutic strategies and discuss the types of treatments that constitute the standard of care for breast cancer.