Polymorphic low penetrance genes along with lifestyle and environmental risk factors are responsible for almost 90% of sporadic breast cancer. Several studies have been conducted on the genetic polymorphic aspects of the disease. Genotoxic compounds implicated in cancer initiation include

• Estrogens
• Diet factors
• Environmental xenobiotics
  • Heterocyclic amines (proteinaceous food cooked at high temperature)
    
  • Aromatic amines (dyes and tobacco smoke)
    
  • Polycyclic aromatic hydrocarbons (incomplete combustion of carbon containing compounds in the atmosphere and tobacco smoke)
    
  • Nitro polycyclic aromatic hydrocarbons (diesel and oil combustion)

These carcinogens (cancer causing agents) are metabolized by the enzymes such as Cytochrome p450, N-Acetyl Transferase and Glutathione S-Transferase and are expressed by the mammary gland. The effect of polymorphisms in the genes encoding these enzymes increase the breast cancer risk and are shown in the table.

Enzyme	Variants	Substrate	Activity	Reference
Cytochrome P450 (CYPs)	CYP1A1,CYP1A2,CYP1B1 CYP2C,CYP2D6,CYP2E1 CYP3A CYP4A CYP17,CYP19	Polycyclic aromatic hydrocarbons and Heterocyclic amines	C - (or) N - hydroxylation	[76], [77], [78]
N - Acetyl Transferase (NAT)	NAT1,NAT2	Heteroyclic Amines	O - Acetylation	[79], [80]
Glutathione S-Transferase (GST)	GST-M1,GST-M3 GST-P1 GST-T1	Heterocyclic Amines	--	[81], [82], [83],[84], [85],[86]

A number of environmental chemicals also play a role in breast cancer initiation which include organochlorines, chlorinated pesticides, polychlorinated biphenyls and polychlorinated dibenzo compounds. They mimic the properties of estrogen which plays an important role in cell differentiation. [87], [88].

Another common genetic variant which increases the risk of breast cancer include Ataxia Telengiectasia which is caused by disruption of ATM gene located on the chromosome 11q22-q23. CtIP is a protein involved in DNA repair machinery and interacts with BRCA1 in regulating the expression of p21 and GADD45 genes. Upon ionizing radiation, the BRCA1 associated protein CtIP, becomes hyperphosphorylated and gets dissociated from BRCA1. This triggers a defect in DNA repair pathway resulting in uncontrolled cell proliferation. [57].