Hypoxia and Hypoxia-Inducible Factors in Normal and Malignant Breast Epithelium

Sammanfattning: Breast cancer treatment is based on tumor and patient related factors such as tumor stage, grade, hormonal status, HER2 status, patient age, and family history to name a few. It is today widely acknowledged that hypoxia and hypoxia-inducible factors (HIF:s) contribute to tumor progression. We therefore set out to explore the impact of hypoxia on mammary epithelial differentiation and what consequences the hypoxic response might have on breast cancer development and behavior. We found that hypoxia induces
a less differentiated, estrogen receptor (ER)-negative/cytokeratin (CK) 19-positive phenotype in mammary cancer cells in vivo and in vitro and suggest that hypoxiainduced dedifferentiation is one of the mechanisms behind hypoxia-driven malignant progression. Hypoxia was also found to significantly impair both morphological and functional differentiation of non-transformed, immortalized epithelial mammary cells grown in three-dimensional cultures. Heterogeneous ER expression in breast cancer was
additionally found to be related to cyclin D1, a cell cycle regulator frequently overexpressed in breast cancer. As cyclin D1 expression was not affected by hypoxia, our findings suggest two separate mechanisms behind varied ER expression in breast cancer. The two pivotal regulators of hypoxic response, HIF-1α and HIF-2α, were analyzed in two cohorts of breast cancer patients and found to be un-correlated suggesting HIF-α
subtype specific mechanisms of induction. Furthermore, HIF-2α was found to be an independent prognostic factor related to distant recurrence.