Breast cancer is the most common malignancy in Pakistani females, whereas it is the second most common cancer in female in other Asian countries. However it is the rare disease found in men and contributes less than 1% of total cancers in males . Many genes have been identified that are associated with breast cancer. In process of tumor initiation and progression, major role is played by mutations, and abnormal amplification of both oncogenes and anti-oncogenes. BRCA1 and BRCA2 are two well-known anti-oncogenes for breast cancer risk [2, 3]. Various mutations in different BRCA1 exons have been reported in literature. Four most frequent BRCA1 mutations (2798 T > C, 3971 G > A, 4921 G > A and 624 C > T) in exon 10 have been found by Sun et al., . Likewise, several mutations in exon 11 were found by Farooq et al.  in BRAC1. About 5 BRAC1 mutations were found by Rasheed et al. [6, 7] which were unique to Pakistani population. In Pakistani people mutations were reported mainly in exon 2, exon 6 (271T > G), exon 11 (1123 T > G) and exon 20 (5231 delG). Chen et al. (2007) conducted meta analysis and found that risk ratio of Ca breast in women above 70 having mutations in BRAC2 and BRAC1 was 49% and 57% respectively . An important tumor suppressor gene is phosphatase and tensin homolog (PTEN) and its functions are cell growth regulation, proliferation, regulation of cell cycle and apoptosis in signal transduction pathways . Many mutations were identified in PTEN gene and 42% were in exon 9 and 4 . Kechagioglou et al., amplified PTEN exons and found 21 mutations in exon 9, 7 and 1 while in exon 5 about 34 mutations were found and all were single based alterations . One of the best processes responsible for the multi-drug resistant phenotype in breast cancer patients is the enhanced ability of cancer cells to transport drugs out of the cell, by the use of one or more ATP-dependent transporters. In human multidrug resistant genes, more than 50 single nucleotide polymorphisms have been observed. Among them, C3435T single nucleotide polymorphism on exon 26 as a silent mutation, found to affect the expression level of MDR1 and consequently drug resistance of cells . Another important member of the ATP-binding cassette (ABC) transporters is ABCG2. The carriers of the A allele of ABCG2 C421A had an increased risk of cancer. Three SNP (34 G > A, 421 C > A and 1143 C > T) were reported by Tandia et al. .
MicroRNAs (miRNAs) are small RNA molecules of nearly 20–25 nucleotides long. They are noncoding RNAs but they are posttranscriptional regulators of gene expression. Studies revealed that they are present intergenic but in some cases they may be in the intronic or exonic regions . In case of humans more than 200 mRNAs have been shown to be involved in cancer progression. Cancer is caused due to alterations in either tumor suppressor or oncogenes and miRNAs are involved in cancers of lung cancer, gastric carcinoma, colon cancer etc. Alterations in miRNA expression have also been found in premalignant stages of cancer . miRNAs may act as tumor suppressor genes when they are downregulated and oncogenes when they are over expressed. Interaction of miR-146a with 3’ UTRs of BRCA1 is involved in regulation of their expression. Upregulation of miR-146a leads to altered expression of BRCA1. Yao et al.,  reported the involvement of micro RNA-146a in many different types of cancer including breast cancer, so by correctly targeting micro RNA-146a, the proper functioning of its target genes can be restored . Micro RNA-21 is one of the most frequently aberrant micro RNAs in human cancer [18, 19]. Among molecules down regulated by micro RNA-21, most important is PTEN. Upregulated miR-21 downregulates PTEN therefore leads to cancer progression. Interaction of miR-146a with 3’ UTRs of BRCA1 is involved in regulation of their expression. Upregulation of miR-146a leads to altered expression of BRCA1. The level of miR-451 is inversely related to mdr1, similarly miR-328 negatively regulates ABCG2 activity. Both of these genes function to reduce the intracellular concentration of a wide spectrum of drugs and antibiotics . But their over expression causes drug resistance of cancer cells to drugs given for breast cancer therapy. Therefore their expression must be regulated by targeting their regulatory miR.
This particular study is going to be focused on mutations in the selected genes (BRCA1, PTEN, ABCG2 and MDR1) and alteration in expression of these genes by selected micro RNAs and subsequently survival analysis and disease free progression will also be studied.