Breast cancer is one of the most common cancers in women worldwide, accounting for approximately 570,000 deaths in 2015. Over 1.5 million women (25% of all women with cancer) are diagnosed with breast cancer every year throughout the world. In America, it’s estimated that 30% of all new cancer cases (252,710) among women are carcinoma in 2017. Breast cancer is metastatic cancer and can commonly transfer to distant organs such as the bone, liver, lung and brain, which mainly accounts for its incurability. Early diagnosis of the disease can cause an honest prognosis and a high survival rate. In North American, the 5-year relative survival rate of breast cancer patients is above 80% due to the timely detection of this disease. Mammography is a widely used screening approach in the detection of breast cancer and proved to help reduce mortality effectively. Other screening methods, such as Magnetic Resonance Imaging (MRI), which is more sensitive than mammography, have also been implemented and studied during the last decade. There’re numerous risk factors such as sex, ageing, estrogen, family history, gene mutations and unhealthy lifestyle, which can increase the possibility of developing breast cancer. Most breast cancers occur in women and the number of cases is 100 times higher in women than that in men. Although the incidence rate of carcinoma in America increases year after year, the death rate decreases thanks to the widespread early screenings and advanced medical therapies. Biological therapies have been developed in recent years and proved to be beneficial for breast cancer Breast tumours usually start from ductal hyperproliferation, and then develop into benign tumours or even metastatic carcinomas after constant stimulation by various carcinogenic factors. Tumour microenvironments such as the stromal influences or macrophages play vital roles in breast cancer initiation and progression.
The mamma of rats might be induced to neoplasms when only the stroma was exposed to carcinogens, not the extracellular matrix or the epithelium 7,8. Macrophages can generate a mutagenic inflammatory microenvironment, which may promote angiogenesis and enable cancer cells to flee immune rejection 9,10. Different DNA methylation patterns have been observed between the normal and tumour-associated microenvironments, indicating that epigenetic modifications in the tumour microenvironment can promote carcinogenesis. Recently, a new subclass of malignant cells within tumours called the cancer stem cells (CSCs) are observed and associated with tumour initiation, escape and recurrence. This small population of cells, which can develop from stem cells or progenitor cells in normal tissues, have self-renewal abilities and are immune to conventional therapies like chemotherapy and radiotherapy. Breast cancer stem cells (bCSCs) were first identified by Ai Hajj and even as few as 100 bCSCs could form new tumours in the immunocompromised mice. bCSCs are more likely to originate from luminal epithelial progenitors instead of basal stem cells. Signalling pathways including Wnt, Notch, Hedgehog, p53, PI3K and HIF are involved in the self-renewal, proliferation and invasion of bCSCs. However, more studies are needed to know bCSCs and to develop novel strategies to directly eliminate the bCSCs .
There are two hypothetical theories for carcinoma initiation and progression: the cancer somatic cell theory and therefore the stochastic theory. The cancer stem cell theory suggests that all tumour subtypes are derived from the same stem cells or transit-amplifying cells (progenitor cells). Acquired genetic and epigenetic mutations in stem cells or progenitor cells will lead to different tumour phenotypes. The stochastic theory is that each tumour subtype is initiated from a single cell type (stem cell, progenitor cell, or differentiated cell). Random mutations can gradually accumulate in any breast cells, leading to their transformation into tumour cells when adequate mutations have accumulated. Although both theories are supported by much data, neither can fully explain the origin of human carcinoma.
Genes associated with carcinoma-:
Lots of genes are identified in reference to carcinoma. Mutations and abnormal amplification of both oncogenes and antioncogenes play key roles within the processes of tumour initiation and progression.
Breast cancer-associated genes 1 and a couple of (BRCA1 and BRCA2) are two famous anti-oncogenes for carcinoma risk. BRCA1 and BRCA2 are located on chromosomes 17q21 and 13q12, respectively. They both encode tumour suppressor proteins. BRCA1 deficiency results in the dysregulation of cell cycle checkpoint, abnormal centrosome duplication, genetic instability and eventually apoptosis. BRCA1 expression is repressed by “pocket proteins” like p130, p107 and therefore the retinoblastoma protein in an E2F-dependent manner. The BRCA1 gene has been shown to make a loop between the promoter, introns, and terminator regions, which regulates the expression of this gene via interactions with its own promoter. BRCA2 protein regulates recombinational repair in DNA double-strand breaks by interacting with RAD51 and DMC1. BRCA2-associated breast cancers are more likely to be high-grade invasive ductal carcinomas, but with a luminal phenotype, the danger of carcinoma might be increased greatly if a private inherits deleterious mutations in either BRCA1 or BRCA2 genes. BRCA1/2 mutations are inherited in an autosomal dominant manner albeit the second allele is normal. Totally, about 20-25% of hereditary breast cancers and 5-10% of all breast cancers are caused by BRCA1/2 mutations. A meta-analysis by Chen showed that the carcinoma risk ratio in women older than 70 years carrying BRCA1 or BRCA2 mutations was 57% and 49%, respectively.
Human epidermal protein receptor 2, also referred to as-erbB-2, is a crucial oncogene in carcinoma and is found on the long arm of human chromosome 17 (17q12). The homologue in mice is Neu, which was first identified in 3-methylcholanthrene induced rat neuroblastoma cells 33. The expression of the HER2 gene is activated mainly through gene amplification and re-arrangement. The HER2 protein is an epidermal protein receptor (EGFR) of the tyrosine kinase family and forms heterodimers with other ligand-bound EGFR family members like Her3 and Her4, thus activating downstream signalling pathways. Knockout of HER2 in mouse models disrupts normal mammary duct formation. Overexpression of HER2, which is detected in about 20% of primary breast cancers, increases the amount of cancer stem cells by PTEN/Akt/mTORC1 signalling and indicates poor clinical outcomes
Epidermal protein Receptor (EGFR)
EGFR, also referred to as c-erbB-1 or Her1 in humans, is found on the short arm of chromosome 7 (7p12). The EGFR protein may be a cell surface glycoprotein of the tyrosine kinase family and is activated by binding to EGF, TGF-α, amphiregulin, betacellulin then on. The downstream signalling pathways of EGFR including PI3K, Ras-Raf-MAPK and JNK are triggered to market cell proliferation, cell invasion, angiogenesis and protect cells against apoptosis Overexpression of EGFR is found in additional than 30% of cases of inflammatory carcinoma (IBC), a really aggressive subtype of carcinoma. Patients with EGFR-positive IBC have a poorer prognosis than those with EGFR-negative tumours quite half the triple-negative carcinoma (TNBC) cases, characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) expression and HER2 amplification even have EGFR overexpression. Therefore, targeting the EGFR pathway could be a promising therapy for these malignant tumours.
This gene is found on the long arm of chromosome 8 (8q24) and encodes for the Myc protein, a transcription factor containing the bHLH/LZ (basic Helix-Loop-Helix Leucine Zipper) domain. Genome-wide screening shows that 15% of all genes are regulated by the Myc protein mainly through the binding on the E-box consensus (CACGTG) and recruiting histone acetyltransferases (HATs) or DNA methyltransferases . A number of the Myc-regulated genes like MTA1, hTERT and PEG10 play vital roles in carcinoma initiation and progression. The overexpression of c-Myc is predominantly observed within the high-grade, invasive stage of breast carcinomas, while no c-Myc amplification is detected within the benign tissues
Modern lifestyles like excessive alcohol consumption and an excessive amount of dietary fat intake can increase the danger of carcinoma. Alcohol consumption can elevate the extent of estrogen-related hormones within the blood and trigger the estrogen receptor pathways. A meta-analysis supported 53 epidemiological studies that indicated that an intake of 35-44 grams of alcohol per day can increase the danger of carcinoma by 32%, with a 7.1% increase within the RR for every additional 10 grams of alcohol per day the fashionable western diet contains an excessive amount of fat and excess intake of fat, especially saturated fat, is related mortality (RR=1.3) and poor prognosis in carcinoma patients. Although the connection between smoking and carcinoma risk remains controversial, mutagens from cigarette smoke are detected within the breast fluid from non-lactating women the danger of carcinoma is additionally elevated in women who both smoke and drink (RR=1.54) Up to now, accumulating pieces of evidence demonstrate that smoking, especially at an early age, features a higher risk of carcinoma occurrence.
Thus far, great advances are made in clinical and theoretical studies of carcinoma
The current prevention methods including screening, chemoprevention and biological prevention are more direct and effective than those within that past. The mortality of carcinoma has decreased. However, carcinoma remains the primary leading explanation cancer death among females aged 20-59 years