Overview of the genetic basis toward early detection of breast cancer

Sumadee De Silva, Kamani Hemamala Tennekoon, Eric Hamilton Karunanayake Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo, Sri Lanka Abstract: Cancer is a socioeconomical burden in any nation. Out of that, breast cancer is identified as the most common malignancy worldwide among women irrespective of age. As women are an important segment in a community, the weakening of their strength toward the development of a nation is a critical problem in each nation. In this review, it was aimed to discuss the characteristics of cancer genome, cancer genetics, and cancer epigenetics in general and then focus on discussing both genetic and nongenetic factors responsible for the predisposition of breast cancer in humans. More emphasis was placed on genes responsible for the early onset of the disease and which can be used as genetic tools in the identification of the disease at an early stage. Then the context of genetic involvement toward the breast cancer occurrence before age of 40 years was highlighted accordingly. In addition to genetic testing, the review paid adequate attention to mention novel liquid biopsy techniques and other clinical, laboratory, and radiologic assessments. These techniques can be used in early detection and recurrence as well as the surveillance of the patients after primary therapies. Keywords: breast cancer, genetic predisposition, early onset, recurrence &nbsp

CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study

Ishani Wickramage,1 Kamani Hemamala Tennekoon,1 Merenchi Arachchige Yasantha Ariyaratne,2 Asanka Sudeshini Hewage,1 Tharmini Sundralingam,1 1Institute of Biochemistry, Molecular Biology and Biotechnology (IBMBB), University of Colombo, Colombo, Sri Lanka; 2National Cancer Institute, Maharagama, Sri Lanka Introduction and aims: Tamoxifen is an adjuvant drug effective in treating hormone ­receptor – positive breast cancer. However, 30%–50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Although association between CYP2D6 polymorphisms and recurrence of breast cancer in patients on tamoxifen had been reported, little evidence exists on association between these polymorphisms and adverse effects to tamoxifen. This study explored the association between CYP2D6 polymorphisms and tamoxifen effects, hitherto not studied in Sri Lanka. Methods: A retrospective preliminary study was carried out on 24 breast cancer patients on tamoxifen for minimally 3 months attending National Cancer Institute, Maharagama, Sri Lanka. They were not on CYP2D6-inhibiting drugs, chemotherapy or other endocrine therapy, and had no conditions that could occur as adverse effects to tamoxifen before starting the therapy. Their blood samples were collected, DNA was extracted and genotyped using SNaPshot Multiplex sequencing based single-nucleotide polymorphism (SNP) assay. Results: SNP/allele frequencies detected: 1846G>A (confirmatory of *4 null allele)=8.3%; 2549delA (confirmatory of *3 null allele)=50%; 100C>T (suggestive of *10 reduced functional allele, in addition to other alleles)=0%; combination of 2988G>A, -1584C and 2850C>T (strongly suggestive of *41 or other reduced functional allele)=4.8%. Occurrence of heterozygous 2988G>A SNP with -1584C and 2850C>T was significantly higher among those with ultrasound-diagnosed fatty liver following the commencement of tamoxifen therapy (P=0.029). Adverse effects occurred at a significantly higher frequency among postmenopausal women (P=0.041). Three patients who developed recurrence of breast cancer had no association with SNPs tested. Conclusions: CYP2D6 SNP combination 2988G>A, -1584C and 2850C>T, strongly suggestive of *41 reduced functional allele, is likely to be useful in predicting occurrence of adverse effect fatty liver in breast cancer patients on tamoxifen, thereby alternative treatment can be considered and lifestyle modifications implemented. Larger sample studies are recommended with the measurement of tamoxifen and metabolite levels. Alternative therapy should be considered for postmenopausal patients. Keywords: fatty-liver, 2988G>A, CYP2D6*41, intermediate-metabolizer, SN

Cytotoxic and Apoptotic Effect of the Decoction of the Aerial Parts of Flueggea leucopyrus on Human Endometrial Carcinoma (AN3CA) Cells

Purpose: To evaluate the anti-cancer potentials of a decoction of Flueggea. leucopyrus (Willd.) on human endometrial carcinoma (AN3CA) cells.Methods: Decoction was prepared by boiling 60 g of the ground plant material in 1.6 L of distilled water for about 3 h to reduce the volume to 200 mL and then freeze dried. The effect of the decoction on AN3CA cells was determined by evaluating its cytotoxicity by 3-(4, 5-dimethylthiazol-2yl) -2, 5-biphenyl tetrazolium bromide (MTT) and sulphorhodamine B (SRB) assays, as well as its ability to modulate apoptosis (microscopic observation of morphological changes, DNA fragmentation and caspase activity). The antioxidant activity of the decoction was also determined by DPPH assay, and its total polyphenolic and flavonoid content.Results: The decoction exerted a significant dose-dependent cytotoxicity on AN3CA cells as evident from MTT assay IC50 values of 22.09 and 14.60 μg/mL at 24 and 48 h post-incubation, respectively; and SRB assay IC50 values of 28.60 and 15.09 μg/mL at 24 and 48 h post-incubation, respectively. The decoction also enhanced apoptosis as shown by enhanced DNA fragmentation, microscopic observation of nuclear condensation, fragmentation and apoptotic bodies and enhanced caspase 3 and 9 activities, as well as moderately increased radical scavenging activity.Conclusion: The cytotoxic and apoptotic effects demonstrated by F. leucopyrus (Willd.) decoction provide supportive evidence for the ethnomedicinal use of this plant for cancer therapy.Keywords: Fleuggea leucopyrus (Willd.), Endometrial carcinoma cells, Cytotoxicity, Apoptosis,Antioxidant, Anti-cance