ABERRANT EXPRESSION OF COL14A1, CELRS3, and CTHRC1 IN BREAST CANCER СELLS.

BACKGROUND: Collagens, which are the major components of the extracellular matrix involved in the regulation of tumor microenvironment, could be differentially expressed in breast cancer (BC) with different transcriptome profiling. AIM: To analyze the transcript level expression of COL1A1, COL5A1, COL10A1, COL11A1, COL12A1, COL14A1, CTHRC1, and CELRS3 genes and the clinical relevance of their differential expression in BC. MATERIALS AND METHODS: The transcript level expression of the genes was analyzed using the quantitative real-time PCR (qPCR) in tumor tissue of 60 BC patients. RESULTS: Overexpression of COL1A1, COL5A1, COL10A1, COL11A1, COL12A1, CTHRC, and CELRS3 anddown-regulated expression of COL14A1 were observed. COL14A1 down-regulation was associated with aggressive, basal, and Her-2/neu BC subtypes (p = 0.031). Overexpression of CELSR3 was found to be associated with the older age of the patients (> 55 years, p = 0.049). Further analysis with the TCGA BC data set has shown a concordance in the differential expression of the above genes. Furthermore, overexpression of CTHRC1 was associated with poor overall survival (OS), particularly with poor prognosis (p = 0.00042) for the luminal BC subtype. On the other hand, CELSR3 overexpression was associated with mucinous tumors and poor prognosis in post-menopausal women. In silicotarget prediction identified several BC-associated miRNAs and members of miR-154, -515, and -10 families to perform a likely regulatory role in the above ECM genes. CONCLUSION: The present study shows that the expression of COL14A1 and CTHRC1 may serve as potential biological markers for the detection of basal BC and the prognosis of survival for patients with the luminal subtype of BC.

Study of Gene Expression Profiles of Breast Cancers in Indian Women.

Breast cancer is the most common cancer among women globally. In India, the incidence of breast cancer has increased significantly during the last two decades with a higher proportion of the disease at a young age compared to the west. To understand the molecular processes underlying breast cancer in Indian women, we analysed gene expression profiles of 29 tumours and 9 controls using microarray. In the present study, we obtained 2413 differentially expressed genes, consisting of overexpressed genes such as COL10A1, COL11A1, MMP1, MMP13, MMP11, GJB2, and CST1 and underexpressed genes such as PLIN1, FABP4, LIPE, AQP7, LEP, ADH1A, ADH1B, and CIDEC. The deregulated pathways include cell cycle, focal adhesion and metastasis, DNA replication, PPAR signaling, and lipid metabolism. Using PAM50 classifier, we demonstrated the existence of molecular subtypes in Indian women. In addition, qPCR validation of expression of metalloproteinase genes, MMP1, MMP3, MMP11, MMP13, MMP14, ADAMTS1, and ADAMTS5 showed concordance with that of the microarray data; wherein we found a significant association of ADAMTS5 down-regulation with older age (≥55 years) of patients. Together, this study reports gene expression profiles of breast tumours from the Indian subcontinent, throwing light on the pathways and genes associated with the breast tumourigenesis in Indian women.

Epidemiology of breast cancer in Indian women.

Breast cancer has ranked number one cancer among Indian females with age adjusted rate as high as 25.8 per 100,000 women and mortality 12.7 per 100,000 women. Data reports from various latest national cancer registries were compared for incidence, mortality rates. The age adjusted incidence rate of carcinoma of the breast was found as high as 41 per 100,000 women for Delhi, followed by Chennai (37.9), Bangalore (34.4) and Thiruvananthapuram District (33.7). A statistically significant increase in age adjusted rate over time (1982-2014) in all the PBCRs namely Bangalore (annual percentage change: 2.84%), Barshi (1.87%), Bhopal (2.00%), Chennai (2.44%), Delhi (1.44%) and Mumbai (1.42%) was observed. Mortality-to-incidence ratio was found to be as high as 66 in rural registries whereas as low as 8 in urban registries. Besides this young age has been found as a major risk factor for breast cancer in Indian women. Breast cancer projection for India during time periods 2020 suggests the number to go as high as 1797900. Better health awareness and availability of breast cancer screening programmes and treatment facilities would cause a favorable and positive clinical picture in the country.

Establishment and characterization of two primary breast cancer cell lines from young Indian breast cancer patients: mutation analysis.

Two novel triple negative breast cancer cell lines, NIPBC-1 and NIPBC-2 were successfully established from primary tumors of two young breast cancer patients aged 39 and 38 years respectively, diagnosed as infiltrating duct carcinoma of breast. Characterization of these cell lines showed luminal origin with expression of epithelial specific antigen and cytokeratin 18 and presence of microfilaments and secretary vesicles, microvilli, tight junctions and desmosomes on ultra-structural analysis. Both the cell lines showed anchorage independent growth and invasion of matrigel coated membranes. Karyotype analysis showed aneuploidy, deletions and multiple rearrangements in chromosomes 7, 9, X and 11 and isochromosomes 17q in both the cell lines. P53 mutational analysis revealed no mutation in the coding region in both the cell lines; however NIPBC-2 cell line showed presence of heterozygous C/G polymorphism, g.417 C > G (NM_000546.5) resulting in Arg/Pro allele at codon 72 of exon 4. Screening for mutations in BRCA1&2 genes revealed presence of three heterozygous polymorphisms in exon 11 of BRCA1 and 2 polymorphisms in exons 11, and14 of BRCA2 gene in both the cell lines. Both the cell lines showed presence of CD 44+/24-breast cancer stem cells and capability of producing mammosphere on culture. The two triple negative breast cancer cell lines established from early onset breast tumors can serve as novel invitro models to study mechanisms underlying breast tumorigenesis in younger age group patients and also identification of new therapeutic modalities targeting cancer stem cells.