1.1 Cancer
Cancer, a devastating disease raised due to uncontrolled cell growth, can commence anywhere in the human body and invades into adjacent tissues to form lumps or masses of tissues. It develops when body’s normal cell division stops working or goes out of control. In some cases, old cells do not die and in its place new cells grow abnormally, forming masses of tumor tissues. Cancer originates due to multiple changes in genes responsible for cellular function. Genetic changes responsible for cancer are at the time of inheritance (Hemminki, 2001; Hemminki et al., 2004) or they can arise as a result of erroneous cell division due to damaged DNA caused by certain environmental exposures that include chemicals in tobacco smoke and some other carcinogens like nitrosamines and polycyclic aromatic hydrocarbons (Hecht et al., 2016). Ionizing and non-ionizing ultraviolet radiation, medical imaging, radon gas and radio frequency radiation emitted from electric power transmission, mobile phones and parallel sources are considered possible carcinogens declared by the World Health Organisation (WHO) in multiple researches on cancer (Frei et al., 2011; Narayanan et al., 2010; Volkow et al., 2011). Several oncoviral infections including Epstein’Barr virus, human papilloma virus, hepatitis B and hepatitis C viruses, herpes virus and human T-cell leukaemia virus-1 account for about18% of cancers. Prolonged exposure to some physical agents like asbestos and hormonal misregulation also contributes to cancer. Decades of investigations on different types of cancers revealed that genetic alterations or mutations are the main driving forces of cellular abnormality. Proto-oncogenes that are involved in normal cell growth and division are likely to be mutated in a large majority of cancers (Loeb and Loeb, 2000). The hallmarks of cancer include several biological potentials such as sustaining proliferative signals, avoiding growth suppressors, resisting cell death, facilitating immortality, activating angiogenesis and enhanced invasion and metastasis (Hanahan and Weinberg, 2011). Cancer develops over an extensive duration by creating different modifications at molecular level and altering phenotypic characteristics. Uncontrolled growth of cancer cells result in genomic instability by promoting cell propagation, angiogenesis, invasion and metastasis.
Figure 1.1 Hallmark of cancer. [Source: Hanahan, D and Weinberg, RA. (2000). Cell 100, 57-70].
1.2. Breast cancer
It is the most common malignant tumor and leading cause of death among women worldwide. It commences in the breast cells and invades to adjacent tissues or metastasizes to other parts of the body (Jemal et al., 2010). One among eight women is diagnosed with breast carcinoma in her life span. It accounts for 16% of all female cancers and 22.9% of invasive cancers in women (Tan et al., 2015). The female breast is mostly compilation of adipose tissues made up of 12’20 lobes. Each of these lobes is consisting of smaller lobules, from which milk is produced in nursing women. These lobes and lobules are connected by milk ducts. Within the adipose tissue, there is a network of ligaments, fibrous connective tissues, nerves, lymph vessels, lymph nodes and blood vessels. This system is collectively known as lymph system, which takes main responsibility of immune system and in turn a favourite spot where cancer can initiate. However, breast cancer can occur at any site in the mammary gland and shows a diverse range of morphology coupled with unique histopathological varieties having specific clinical features. The major progression of breast cancer is a stepwise development from atypical ductal hyperplasia to ductal carcinoma in situ (DCIS), followed by invasive breast cancer that finally turns into metastasis (Figure 1.2) (Wellings and Jensen, 1973).
Figure 1.2. Schematic representation of breast cancer development. [Source: Rivenbark, A. G., O’Connor, S. M. and Coleman, W. B. (2013). Am J Pathol 183, 1113-24.]
1.2.1. Morphological classification of breast cancer
Breast cancer can be classified into three types based on the way the cancer cells look under the microscope: non-invasive, invasive and metastatic breast carcinoma. Cancer that begins in the lactiferous duct or milk duct, known as ductal carcinoma in situ (DCIS). It is the most frequently occurring non-invasive or pre-invasive carcinoma. DCIS is further classified into three subtypes depending on their architectural pattern such as solid, cribriform, papillary, and micro papillary depending of tumour grade (high, intermediate and low) and the presence or absence of comedo necrosis. DCIS corresponds to a transitional step between normal breast tissues and invasive breast cancer (Virnig et al., 2010). On the other hand, cancer that begins in the lobules, also known as lobular carcinoma, is less common type of non-invasive carcinoma. This type of breast carcinoma metastasizes outside the breast. Invasive or infiltrating ductal carcinoma (IDC) is commonly occurring breast cancer which is able to metastasize to other parts of the body through the bloodstream and lymphatic system. The most common subtypes of invasive carcinoma are invasive lobular, tubular, metaplastic, cribriform, papillary and micro papillary carcinoma. Invasive lobular carcinoma (ILC) starts in the milk-producing glands and spread to other parts of the body making it difficult to detect by mammogram (Talman et al., 2007). Tubular carcinoma and invasive cribriform carcinoma occur within milk duct and extend into nearby tissues. These types of tumors are usually smaller with low-grade malignancy (Rakha et al., 2010). Metaplastic carcinoma characterizes a group of unrelated invasive breast cancers that display differentiation of the tumor cells into squamous or mesenchymal characteristics including spindle, chondroid, osseous, and rhabdomyoid cells (Lee et al., 2012). Adenoid cystic carcinoma is the most recurrently occurring salivary-type breast tumor of the breast with low-grade malignancy (Foschini and Krausz, 2010). Invasive papillary breast carcinoma is a type of adenocarcinoma having papillary morphology whereas invasive micro papillary carcinoma has been categorised into luminal-type having a tendency for lympho-vascular invasion and regional lymph-node metastasis (Chen et al., 2008).