Life Style, Molecular Pathology, and Breast Cancer Risk

Abstract: The breast cancer diagnosis covers a wide range of tumours with different geno- and phenotypic characteristics. The diversity among studies on life-style factors and their impact on breast cancer risk might be clarified by recognizing breast cancer as a heterogeneous disease. A major aim of this thesis was to investigate the association between several life-style factors and subsequent breast cancer risk according to pathological- and tumour biological characteristics. Further, we examined two novel tumour markers with respect to their relation to established tumour characteristics, estrogen-related-life-style-factors, and/or response to endocrine breast cancer treatment. The thesis is predominantly based on breast cancer cases from the Malmö Diet and Cancer Study, a prospective cohort study including 17 035 women with baseline examinations performed 1991-1996. The study cohort was followed by record-linkage with national cancer registries and at the end of follow-up in 2004, 622 women had been diagnosed with breast cancer. Additionally, we used a consecutive cohort of 512 women diagnosed with breast cancer at the Malmö University Hospital 1988 and 1992. Immunohistochemical assessments of different tumour markers were performed using the tissue microarray (TMA) technique. Analyses of dietary habits and tumour characteristics revealed an association between low energy intakes and a more aggressive histopathological phenotype as well as over-expression of the cell cycle regulating protein, cyclin D1. A low fat intake showed similar associations to tumour characteristics. The use of combined (estrogen-progestin) hormone replacement therapy was associated with an increased risk of breast cancer, although with comparatively favourable prognostics factors, such as lobular type, low grade, low proliferation, negative/low cyclin D1 expression and maintained expression of the tumour suppressor gene, p27. In a similar way obesity was associated with an increased risk of less aggressive breast cancer characterised by lobular type, grade II, low proliferation, HER2 negativity, ER?+, PgR+, but negative ER? expression. The enzyme HMG-CoA reductase was differentially expressed in breast cancer and high expression was associated with a smaller tumour size, low grade, low proliferation, and expression of ER? and ER?, but not PgR. Estrogen-related factors, such as obesity and use of hormonal replacement, were associated with an increased risk of tumours with high expression of HMG-CoA reductase. The novel estrogen receptor, ER?, was associated with expression of ER? and PgR, but not with other established prognostic factors, such as tumour size, grade, and lymph node metastases. Co-expression of both estrogen receptors indicated an improved response to endocrine therapy.