Immunophenotyping of hereditary breast cancer

Hereditary breast cancer runs in families where several family members in different generations are affected. Most of these breast cancers are caused by mutations in the high penetrance genes BRCA1 and BRCA2 which account for about 5% of all breast cancers. However, mutations in BRCA1 and BRCA2 may be missed, and small families and sometimes insufficient medical records may cause uninformative family history. This thesis aimed to investigate the immunoprofile of hereditary breast cancers caused by germline mutations in the BRCA1 or BRCA2 genes in order to identify patients and families eligible for mutation screening. In addition, such studies on hereditary precursors could help to better understand hereditary breast carcinogenesis and identify new therapeutic targets. We started with evaluating a panel of clinicopathological variables to classify breast cancers as hereditary or sporadic using a multivariate approach. Most of the investigated markers were expressed in line with earlier data. However, we were the first to describe the high expression of EGFR in BRCA1 and BRCA2 related breast cancers. In addition, the observed high cyclin A expression is another useful proliferation marker in BRCA1 related breast cancers, and has been herewith established for the first time. Although our data were based on only five cases of BRCA2-related breast cancers, the cyclin D1 expression in these tumours was remarkably high. As such, most invasive breast carcinomas can be classified as sporadic or BRCA1 related with a high degree of certainty using a decision tree based on age, Ki67 and EGFR. Furthermore, we are the first to report that in BRCA1 and BRCA2 mutation carriers the immunoprofile of ductal carcinoma in situ (DCIS), a premalignant lesion, parallels the accompanying invasive cancer lesion, underlining that DCIS is probably a direct precursor lesion in these patients. In addition, crucial carcinogenetic events leading to these phenotypes apparently occur at an early stage in hereditary predisposed patients, most likely even before the stage of DCIS. We describe the novel finding of loss of expression of FANCD2, a Fanconi anaemia gene previously implicated in breast cancer in mice, in hereditary and sporadic invasive breast cancer, indicating that somatic inactivating (epi)genetic events in FANCD2 may occur in both sporadic and hereditary breast carcinogenesis. Our results do however not indicate that somatic (epi)genetic changes in FANCD2 are a frequent secondary carcinogenetic event in BRCA1 germline mutated patients. The expression of HIF-1?, the key regulator of the hypoxia response, in hereditary breast cancer is for the first time reported in comparison with sporadic breast cancer. 90% of BRCA1 germline mutation related breast cancers showed overexpression of HIF-1?, a percentage significantly higher than in sporadic controls. The overexpression of HIF-1? in BRCA1 related breast cancers is a frequent event and is likely hypoxia regulated, suggesting that the HIF-1? pathway plays a role in the BRCA-1 carcinogenesis and progression. All these findings will lead to improved discrimination of the BRCA1 and BRCA2 related breast cancer. Furthermore, the new biomarkers may serve as therapeutic targets for BRCA1 and BRCA2 related breast cancers.