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Title: A molecular analysis of the oestrogen receptor and surrounding chromosomal region in early breast cancer
Author: Chappell, Stephen
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 1997
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Despite extensive research, the pathways of breast cancer development remain largely unknown. Identification of key genetic alterations, particularly at early stages of the disease, are central to elucidating the development of the disease.;Analyses for abnormal forms of the oestrogen receptor (ER) were performed to determine if they may be functionally important in the evolution of breast cancer. Forty four mammographically detected, node negative, 15mm of less, moderately or well differentiated, invasive carcinomas were screened b RT-PCR and single stranded conformational Polymorphism analysis, identifying variant forms of exon 3, 5 and 7 in addition to 3 missense mutations. ER splice variants were detected in 15/44 tumours and included exon 5 (2/44), exon 3 (4/44) and exon 7 (13/44). 10/37 grade I and II tumours had variants compared with 5/7 grade III tumours. In addition, 11/39 ER+ and either progesterone (PgR)+ or PgR- tumours had variants compared with 4/5 ER-/PgR-tumours.;Pure populations of tumour cells were microdissected from well defined groups of breast lesions including ductal carcinoma in situ (DCIA), tubular carcinomas, and a similar tumour group screened for variant ERs, and analysed for alterations to polymorphic microsatellite sequences within, and flanking the ER gene (6q25.1-27) itself. This enabled evaluation of loss of heterozygosity (LOH) indicating the presence of tumour suppressor genes, and microsatellite instability (MI) indicative of a mutator phenotype in colorectal cancers.;Frequent LOH, apart from the M6P/IGF2R locus, was observed for all types and grades of disease studied; identifying loss in this region as an early event involved in breast development/progression. In comparison, MI at multiple loci and LOH at the M6P/IGF2R were only found in high grade DCIS. LOH at this chromosomal interval in all types and grade of disease suggests inactivation of other as of yet uncharacterised tumour suppressor genes mapped on chromosome 6q25.1-27.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available