The human female mammary gland develops through key stages in life particularly during fetal growth, infancy, puberty, pregnancy, lactation and postmenopausal regression . The formation of the mammary crest and primitive mammary buds begin during embryonic life through a series of highly ordered events regulated by growth factors and hormones [reviewed in ]. Paired ectodermal thickenings, known as mammary ridges, develop from the axilla to the groin on the anterior surface of the embryo by 6 weeks of gestation. These mammary ridges initially appear in multiple pairs along the milk line but most ridges regress during development except for one pair in the pectoral region, where the two mammary glands subsequently develops. The mammary parenchyma then invades the stroma to form the mammary crest at week 7 and 8 of gestation. Between 10 and 12 weeks of gestation, the mammary ridge begins to differentiate and proliferate into mammary epithelial buds. The mammary buds continue to proliferate during weeks 13 to 20 of gestation to form branches and secondary buds. These secondary buds gradually elongate into 15 to 25 solid cords by 20 weeks gestation . At 32 weeks, placental hormones enter the fetal circulation to initiate canalisation of the solid cords and formation of the lactiferous ducts (Hovey et al. 2002). The ducts enlarge to form lactiferous sinuses and converge into the nipple area. The periductal stroma increases in density along with limited lobulo-alveolar development, while the areola acquires a slight pigmentation during the final 8 weeks of gestation (Naccarato et al. 2000). The infant's mammary gland produces small amount of colostrum shortly after birth as a result of maternal lactogenic hormones present in the fetal circulation. The decrease in infant prolactin levels coincide with the spontaneous regression of the infant's mammary gland within 4 weeks postpartum .
The neonatal breast consists of rudimentary ducts that remain quiescent until early childhood. Growth of the mammary epithelium and stroma continues at puberty, between the age of 8 to 12 years . Puberty induces rapid breast growth as a result of increasing levels of secreted steroid hormones, primarily oestrogen in the form of 17β-oestradiol, driven by ovulation and the establishment of menstrual cycles . The increased deposition of adipose tissue within the gland and vasculature enhancement causes an increase in breast size. Circulating oestrogen stimulates elongation of the existing ducts and branching into secondary ducts. The growing and dividing ducts form rounded terminal end buds, from which bi-layered epithelial buds appear and form lobules . The lobulo-alveolar development continues gradually during adolescence until approximately the age of 35 years, resulting in three distinct types of lobules in the mature adult breast .
Breast development culminates during pregnancy and lactation cycle when the mammary gland matures into a functional milk-secretory organ through complete remodelling of the breast. Increased levels of circulating lactogenic hormone complex (oestrogen, progesterone and prolactin) directly regulate this maturation stage by inducing ductal branching, alveolar morphogenesis and secretory differentiation . By the second trimester of pregnancy, mammary epithelial cells in the luminal layer of the alveolar differentiate into milk-producing lactocytes. Secretory activation and milk synthesis occurs after parturition, triggered by the decrease in circulating progesterone and further increase in prolactin. Cessation of milk removal causes the mammary gland to transition into a resting non-lactating state through post-lactational involution . Clearing of the mammary alveolar cells occur during involution, allowing the breast to regress into a non-functional organ until the next pregnancy and lactation cycle. The breast undergoes a second phase of involution (post-menopausal involution) triggered by ovarian function decay during menopause, which is characterised by the decrease of glandular breast tissue and increase in the adipose surrounding tissue (Hutson et al. 1985).
1.1.2 Anatomy of the breast
The breast overlies the pectoralis major muscle positioned between the second and the sixth rib bone. The blood supply of the breast is derived from the internal mammary artery (60%) and the lateral thoracic artery (30%) . Lymphatic drainage of the breast drains lymph from the breast to the axillary nodes and the internal mammary nodes (Hultborn et al. 1955; Turner-Warwick 1955).
The adult breast is composed of secretory and fatty tissue supported by loose fibrous connective tissue known as Cooper's ligaments . The secretory tissue is made of 15-25 lobes that converge at the nipple in a radial arrangement and a ductal system that drains the alveoli to transport milk to the nipple. Each lobe comprise of lobules that contain 10-100 alveoli that produces and stores milk. Numerous small ductules that drain the alveoli merge into one main duct, which dilates to form the lactiferous sinus, then narrows and opens onto the nipple surface (Venta et al. 1994).
E. Lobules
F. Lymph nodes
G. Areola
A. Pectoralis major muscle
B. Adipose tissue
C. Lactiferous sinus
D. Ducts
1.2 Breast cancer
1.2.1 Epidemiology
Breast cancer is the most common cancer in the UK since 1997 even though its incidence is rare in men. In 2010, 49564 women and 397 men in the UK were diagnosed with invasive breast cancer, causing 11633 death . Breast cancer accounts for 31% of all female cancers and the lifetime risk for developing breast cancer is 1 in 8. Breast cancer is the second most common cause of cancer death among women in the UK after lung cancer; however, its survival rates have improved over these past 40 years. Five-year survival rate for breast cancer has increased from 52% patients diagnosed in 1971-1975 to 85.1% patients diagnosed in 2005-2009 . Survival rate of this disease largely relies on the cancer stage at the point of diagnosis, where 90% of women diagnosed at stage I breast cancer survive beyond five years compared to only 10% when diagnosed at stage IV breast cancer .
1.2.2 Risk factors
There is no single definitive factor that is responsible for the majority of breast cancer; however there are several established factors that strongly increase a woman's risk of developing the disease. The strongest risk factor for breast cancer is age, where incidence and mortality increases as women get older. Based on the estimates for 2008, the risk of developing breast cancer increases 10 times in women from age 29 to age 39, 4 times from age 39 to age 49, then doubles the next 10 years until menopause when the rate of increase slows dramatically (Sasieni et al. 2011; Cancer Research UK 2012). Environmental factor in the form of geographical variation presents as another important risk factor, as women in developed countries have five times increased risk of breast cancer compared to women from less developed countries. Interestingly, studies of migrants from eastern to western countries show that the risk of breast cancer in migrants assume that of the host country within one or two generations, indicating that environmental factors outweigh genetic factors (McPherson et al. 2000). While genetic predisposition doubles the risk of breast cancer in a woman with affected first degree relative, it only contributes up to 10% of breast cancer in western countries (Pharoah et al. 1997). Critical analysis of epidemiological studies for familial breast cancer have revealed that 8 out of 9 women who develop breast cancer do not have affected first degree relative and although women with affected close relative are at increased risk, most will never develop breast cancer . Hereditary factors only contribute to a quarter of an individual's susceptibility to breast cancer while environmental and lifestyle factors contribute to the remaining three-quarters (Lichtenstein et al. 2000).
Genetic predisposition to breast cancer originally derived from evidence of cancer clustering in families and increased cancer risk in individuals with certain genetically linked diseases. Germline mutations in at least five genes have been identified to predispose an individual to breast cancer: breast cancer 1 (BRCA1), BRCA2, tumour protein 53 (TP53), phosphate and tensin homolog (PTEN) and ataxia telangiectasia mutated (ATM) (Malkin et al. 1990; Swift et al. 1991; Nelen et al. 1996; Peto et al. 1999). Mutations in BRCA1 and BRCA2 are high penetrance genes that increase the risk of breast and ovarian cancer, and account for 2% of all breast cancer cases. Germline mutations in TP53 predispose to Li-Fraumeni cancer syndrome, a condition which encompasses childhood sarcoma, brain tumours and early onset breast cancer. Mutations in PTEN are responsible for Cowden syndrome, which is mainly characterised by breast cancer and heterozygous carriers of ATM have an increased risk of breast cancer.
Many reproductive factors that influence breast cancer risk are closely linked to prolonged exposure to hormones. Early menarche and late menopause extends the relative exposure of the breasts to high concentrations of endogenous oestradiol, thus increasing the risk of breast cancer. High oestradiol concentrations and obesity in postmenopausal women are also positively associated with breast cancer risk . On the other hand, increased childbearing and prolonged breastfeeding have a protective effect that reduces the risk of breast cancer . The intake of exogenous hormones through oral contraceptive slightly increase the relative risk of developing breast cancer in current users, however the excess risk falls after cessation of use and becomes insignificant after more than 10 years cessation . Hormone replacement therapy (HRT) substantially increases oestrogen concentration in the serum and incidentally increases the relative risk of breast cancer compared to non-users. Current users and users of oestrogen-progestagen therapy have increased risk of breast cancer that is enhanced by the duration of use but diminished after cessation .
Clinical factors such as breast density and benign breast disease also contributes to the risk of developing breast cancer. Breast density is defined by its proportion of fatty tissue, where low breast density correlates with high proportion of fatty tissue and vice versa. Women with high breast density have five times higher risk of breast cancer than women with low breast density . Benign breast diseases that stem from non-proliferative lesions are associated to none or little increase in breast cancer risk. Women with proliferative lesions without atypia have two-fold increased risk, while those with atypical hyperplasia have at least four-fold increased risk (Hartmann et al. 2005).
Other modifiable lifestyle factors that increase the risk of breast cancer include high body mass index, lack of physical activity, high alcohol consumption, high fat diet and smoking before the age of 20 .
1.2.3 Breast screening
The prognosis of breast cancer heavily depends on the stage of the disease during diagnosis; hence routine breast screening is important to detect early cancer changes with the aim of increasing survival rates. In the UK, the National Health Service Breast Screening Programme (NHSBSP) was set up in 1988 as a response to the recommendation of 'The Forrest Report' to implement a population based screening programme . The programme uses mammogram to screen for breast cancer every three years, initially to all women aged 50 to 64. Since 2004, this service has been extended to include women aged 65 to 70 and presently, all women aged 47 to 73 are eligible for breast screening. An assessment for the period 1990 to 1998 on the impact of NHSBSP revealed that the programme contributed to a substantial reduction on breast cancer mortality rate in women aged 55 to 69 (Blanks et al. 2000). Controversy about this programme has emerged in the recent years as questions were raised about the value of breast screening and possible harmful effects to some women. Mammographic screening is effective in detecting lesions in the breast but lacks the specificity to differentiate between low grade in situ carcinoma and high grade invasive cancer. This inevitably leads to overdiagnosis and overtreatment of cancer in some women who would never have presented clinically. Mammography itself carries a small carcinogenic risk from radiation and has been estimated to cause 3 to 6 extra breast cancers for every 10000 women enrolled in the screening programme (Cancer Research UK 2012). As a result, a group of independent experts were gathered to review the benefits and effectiveness of the programme. The review panel found that out of 15500 breast cancers diagnosed through screening, 4000 cases are overdiagnosed while 1300 breast cancer deaths are prevented each year (Cancer Research UK 2012). The panel concluded that the NHSBSP has significant benefit to the country as a whole and justifies the continuance of the screening programme.
1.2.4 Pathology
The prognosis of breast cancer heavily depends on the stage of the disease during
Characterisation=pathology
Origin=aetiology
http://ww5.komen.org/breastcancer/diagnosis.html
http://qap.sdsu.edu/education/bcrl/Bcrl_anatpath/bcrl_anatpath_index.html
http://m.breastcancer.org/Images/Pathology_Report_Bro_V14_FINAL_tcm8-333315.pdf
The complexity of breast cancer arises from the fact that there is no single factor
Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. -Jason Caroll
