Current Advances in Breast Cancer Research: A Molecular Approach

The burden of breast cancer incidence and related mortality is a major health problem worldwide. In the last few years, the incidence and mortality rate of breast cancer have grown very rapidly in many developing countries and also slowly in developed nations. According to GLOBOCAN 2018 status report, the global cancer burden is estimated to have risen to 18.1 million new cases and 9.6 million deaths in 2018. The etiology of breast cancer depends upon several factors and includes age, genetic, environmental, radiation, breastfeeding, diet, and lifestyle factors, etc. The reasons behind the high breast cancer-related mortality are due to the lack of basic knowledge and awareness about breast cancer, less efficient diagnosis, late screening, poor health facilities, and limited access to treatment in developing countries. In this chapter, we summarize key studies on breast cancer epidemiology, types of breast cancer, risk factors, diagnosis, screening tools, predictive marker, surgery, chemotherapy, radiotherapy, hormonal therapy, targeted therapy, and preventative methods on breast cancer over the past years. These integrated findings may help protect and fight against breast cancer.

Tissue diagnosis has been recognized as the gold standard method of diagnosing breast cancer; however, over the last few decades, radiologic imaging has taken the center-stage in pre-operative diagnosis of breast cancer. Radiological imaging tools play a crucial role in not only early detection of breast cancer and staging but also help the surgeons in chalking out the surgical plan and later also in surveillance of the patients. While the advancements in imaging have improved the rate of early detection of breast cancer, ‘false alarms’ raised due to limitations of existing imaging methods are an important area of concern. The purpose of this chapter is to provide an overview of the capabilities and limitations of the current imaging techniques in breast cancer.

The molecular techniques play an important role in the diagnosis and treatment of breast cancer. Recent advances in molecular techniques have contributed significantly to understanding tumor biology, tumor heterogeneity, identification of different biomarkers, and discovery of new therapeutic measures and improvement in overall survival, especially in specific subsets of breast cancer. There are other challenging areas in breast cancer research, such as the development of treatments for the highly aggressive triple-negative breast cancer subtype, chemotherapy-resistant cancer stem cell subpopulation, and male breast cancer. New knowledge emerging from researches in genetics, proteomics, and metabolomics offers a promising opportunity for the identification of new biomarkers, and to find novel targets that could facilitate future therapeutic interventions.

Breast cancer accounts for a massive and very frequently occurring disease among females throughout the world. In spite of several approaches for the detection of cancer at an early stage and diverse curative strategies that are coming out, the discovery of a potent, efficacious, and unique biomarker is requisite for precise diagnosis at an early stage, as prognostic predictors and as a marker of the development of therapeutic resistance. In the current scenario, the availability of validated breast cancer biomarkers is almost nil. Barely a handful of biomarkers that have a practical advantage in terms of prognosis and diagnosis include estrogen receptor (ER), progesterone receptor (PR), and HER-2 with limitations. Therefore, the urge of precise biomarkers for the detection of breast cancer stands in need. The progress and utilization of proteomic techniques for the discovery of new protein biomarkers have revolutionized the way of understanding the biology and the associated pathways involved in the progression of the disease. With the help of proteomics, now plenty of prospective protein and peptide biomarkers can be identified from the samples using high-throughput analysis. In this chapter, we covered the techniques, which are routinely employed for treatment, diagnosis, and prognosis of breast cancer with all their benefits and drawbacks. It also includes recent advancements in the field of proteomics and their utility in search of new cancer biomarkers.

Post-translational modifications (PTMs) regulate vital cellular processes such as signaling, proteasomal mediated degradation of proteins, and transcription. Deregulation of post-translational modifications (PTMs) has been proven to have a strong association with breast cancer development. Aberrant PTMs can promote carcinogenesis by perturbing normal cellular homeostasis. The current literature review showed that breast cancer cells displayed abnormal ubiquitination, glycosylation, phosphorylation, and SUMOylation patterns. Breast cancer cells also exhibited stable modifications in histone proteins and DNA. These epigenetic modifications can directly affect the expression of cell cycle regulators by disrupting the transcriptional state of the genome. The current chapter summarizes the involvement of PTMs in carcinogenesis and the mechanism by which PTMs promote abnormal cell growth. Enzymes responsible for aberrant PTMs could be targeted to reduce the severity of the disease and may improve the prognosis of breast cancer.

Breast cancer in women is the most frequent cancer with the highest mortality worldwide. The risk factor includes aging, family history, genetic predisposition, and hormone factor. In recent years, many new gene signatures have been identified, which have a profound effect on breast cancer initiation and progression. Extensive research has been done in the past five decades in understanding breast cancer biology through genomics and proteomics. All these comprehensive studies from breast cancer patients elucidate heterogeneity of disease as one of the complex problems in its treatment and management. The outburst of molecular information has led to an understanding of the biological diversity of breast cancer. The involvement of various genes at different steps of cancer progression, such as proliferation, evading apoptosis, migration, immunosuppression, and chemoresistance, have been described in this chapter. With the advent of miRNA and splicing factors, new differential regulators of genes have been identified in breast cancer. The breast cancer therapeutic approach can be accomplished by identifying the oncogene and tumor suppressor genes at an early stage of the disease. Elucidation of novel genes in breast cancer will lead to identifying new molecular pathways that may be targeted for its treatment. For the prognostic and diagnostic treatment of breast cancer it is very important to identify newer genomic fingerprints and to develop novel therapeutic targets against them. Our main goal is to make available inclusive understanding of molecular mechanisms and hallmarks of breast carcinogenesis.

Cancer cells devise different mechanisms to undergo aberrant cell division. Dysregulated signaling pathways and metabolic reprogramming are the two key mechanisms leading to cancer development. The role of metabolic dysregulation has been well known in cell proliferation, metastasis, and resistance to therapy, eventually leading to tumor progression. The dysregulation of enzyme activity and biochemical pathways have emerged as major factors in the metabolic reprogramming of breast cancer. The abnormal changes in the level of metabolites are mechanistically associated with the metabolism of cancer. Quantitative research studies have provided a list of metabolic biomarkers, which have a promising role in the early detection of breast cancer as well as in its therapy. Many of the current research studies are directed towards understanding the intricacies of metabolism in cancer cell proliferation. This chapter gives an overview of breast cancer metabolism with updated information and describes how deregulated metabolism plays a key role in the oncogenic cascade leading to the neoplastic transformation of cells.

Lifestyle-based changes such as diet, physical inactivity, smoking, and alcohol consumption are some key risk factors of breast cancer among women. Changes in the lifestyle disrupt redox homeostasis, particularly decreasing the ability of the body to detoxify harmful free radicals. Therefore, an imbalance between these finely tuned mechanisms results in the formation of excessive reactive oxygen species (ROS). These elevated levels of ROS may promote breast cancer development and progression. Over the centuries, the way of living has changed drastically worldwide, and several lifestyle factors have evolved as a threat and risk factor for cancer in humans. Most of these lifestyle factors, e.g., smoking, alcohol consumption, physical inactivity, poor nutrition, etc., have been associated with the rise in breast cancer incidences globally. A large number of accumulating evidence from clinical and epidemiological studies strongly suggest the link between lifestyle factors and the incidence of breast cancer in women. Some changes in lifestyles increase the risk of breast cancer in both premenopausal and postmenopausal women. However, the period between menarche to the birth of the first child is the most vulnerable phase in women's lives. Lifestyle factors drive carcinogenesis through various mechanisms. Among them, ROS-mediated oxidative damage plays a significant role in breast cancer development. Here, in this chapter, we have discussed the most relevant lifestyle factors associated with breast carcinogenesis in women. Also, we have discussed how these lifestyle factors modulate redox homeostasis to elicit oxidative damage-induced carcinogenesis. A better understanding of the association between lifestyle factors and breast cancer may enable us to identify critical factors that can play a significant role in breast carcinogenesis.

The epithelial to mesenchymal transition (EMT) is a key cellular event that plays a pivotal role in promoting metastatic disease and tumor recurrence among solid malignancies. EMT is involved not only in essential cellular processes, including embryonic development and tissue remodeling, but also in inducing tumorigenesis. Breast cancer (BC) is the most prevalent cancer in women globally, and the main causes of breast cancer mortality are metastasis and recurrence. EMT plays an imperative role in enhancing invasion, following metastasis. Integrated changes in several cell signaling events lead to an epithelial to mesenchymal phenotypic shift and provide cells with more migratory and invasive properties that eventually results in metastatic colonization at a secondary site. However, the present knowledge about the cross-talk of multi-faceted signaling pathways and associated crucial transcription factors is yet to be understood. Understanding the cellular complexities of EMT will provide valuable insights for the therapeutic targeting of aggressive breast cancers, and in the development of novel biomarkers to delimit malignancies with greater chances of metastasis and recurrence.

Among the plethora of human malignancies, breast cancer is one of the most prevalent cancers diagnosed in women worldwide. The early detection of breast cancer with current techniques has significantly reduced the mortality rate in the last decade. Nonetheless, various drawbacks presented by these techniques remain as one of the foremost hurdles in the proper clinical management of the condition. The discovery and utilization of highly specific, minimally invasive unique biomarkers would greatly aid an efficient diagnosis and prognosis of breast cancer. The differential expressions of miRNAs also play well-studied roles in the progression and metastasis of the condition. The chapter outlines the clinical importance of miRNAs-based biomarkers in the early detection and prognosis of breast cancer and reviews the different subtypes involved. The role of miRNAs in modulating various cellular processes during the progression and metastasis of breast cancer has been discussed. Finally, the importance of an integrated omics approach in identifying novel targets of miRNAs is also elaborated upon.

Calcium (Ca2+) signaling plays an important role in every aspect of cellular physiology, including cell proliferation, cell death, and cell motility. In the cellular environment, calcium signaling is tightly regulated to achieve a specific cellular response. Dysregulation in cell proliferation and cell death are crucial events in cancer evolution. There are several reports which have established the central role of calcium signaling in acquiring the hallmarks of cancer. Calcium signaling has been shown to be linked with several proteins and pathways, which are involved in the progression and advancement of breast cancer, including RANK/RANKL signaling pathway, EGFR and CAMK signaling, Rap2B, ERK1/2 signaling, Ca2+ influx pathways, MCU proteins, PTHrP, calmodulin, PARP1, NFAT, calpain, mitogen-activated protein kinase (MAPK), calmodulin-dependent protein kinase II (CaMKII), epithelial-mesenchymal transition (EMT), phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP3), vascular endothelial growth factor (VEGF), estrogen, and estrogen receptor. In the recent past, several studies presented good enough pieces of evidence suggesting Ca2+ channels and transporters as a potential therapeutic target of breast cancer treatment. Therefore, in light of previous knowledge, in this chapter, we will discuss the role of Ca2+ signaling in breast cancer and its therapeutic implication as to the current perspective of breast cancer treatment.

The powerhouse of the cell, mitochondria play several cellular functions, and it also regulates the physiological adjustment of the body. The deregulation of any of the key factors in the regulation pathway of energy production or cellular metabolism leads to disease conditions and, sometimes even cancer. Several studies emphasize the fact that the alteration in metabolic pathways, generate or evoke cancer susceptibility including breast cancer. Among the several cancers, breast cancer is a major concern in the female population. Thus, the alteration of any mitochondrial factors or metabolites associated with the mitochondrial energy cycle, the changes in breast cancer development or progression of metastasis is high. Mitochondrial regulation could be a promising therapeutic approach in the treatment of breast cancer.

Breast cancer is the most common type of malignancy in women worldwide. There are several factors associated with breast cancer for manifesting a heterogeneous disease in nature. Chemotherapeutic drugs significantly reduce the mortality rate of breast cancer. The recent development of chemotherapeutic drugs is targeting heterogeneity by including hormone receptors, expression of genes, epidermal growth factors, etc. The therapeutic response is dependent on a variety of factors, including stages, subtypes, metastasis, etc. For example,- endocrine therapy is preferred for positive hormone response in luminal breast cancer. In the recent therapeutic regimens, CDK4/6 quenchers are emerged, which regulate cell cycle by interacting with cyclin D1. It is also because, in the case of resistant hormonal therapy, tumors still showed its dependency on CDK4/6- cyclin D1 for proliferation. Apart from chemotherapy, immunotherapy is one of the emerging therapeutical regimens for breast cancer. There are also a number of vaccination approaches against breast cancer, including Nelipepimut–S, derived from the extracellular domain of the human epidermal factor receptor, which is used as a vaccine to prevent the reoccurrence of refractory breast cancer. Epithelial-to-mesenchymal transition (EMT) is a crucial mechanism for breast cancer progression. Currently, EMT inhibitor is used for preclinical testing to further used as a drug molecule to treat breast cancer. Thus, the advancement of chemo- or immunotherapy can substitute over invasive treatment strategies such as the surgical method for the treatment of breast cancer.

In this chapter, we thoroughly review the current developments and challenges in the field of tissue engineering of normal and breast cancer cells. We also briefly describe the current advances in cell culture techniques and common biomaterials, which are useful in the field of tissue engineering. Further, the need for a new microencapsulation technology of cells utilizing the microfluidic method is illustrated. Moreover, the most recent applications of cell-laden microcapsules in tissue engineering are summarized. Lastly, the chapter is concluded with an outline of the future prospective.