HIF-1α and NOTCH signaling in ductal and lobular carcinomas of the breast

NOTCH signaling is involved in every step of metazoan development and maintenance of adult tissue homeostasis. It is frequently deregulated by mutations and overexpression in different cancer types including solid tumors such as breast cancer. Another common feature of solid tumors is hypoxia, which occurs due to defective or insufficient vascularization. Hypoxia-inducible factors (HIFs) are key regulators of the homeostatic response to low oxygen levels. HIF-1 alpha is overexpressed in many solid tumors, including breast cancer. Hypoxia-induced stabilization of HIF transcription factors has been shown to lead to NOTCH activation in vitro in different contexts and tissues, causing differentiation arrest and induction of proliferation and migration. Since the link between HIF-1 alpha and NOTCH signalling has hardly been studied, we set out to closely investigate associations between the expression of HIF-1 alpha and NOTCH pathway members in primary and metastatic human breast cancer specimens and their prognostic value. Co-expression of NOTCH1 intracellular domain (N1ICD) and HIF-1 alpha was associated with a high grade and a high proliferation rate in invasive breast cancer. HIF-1 alpha expression was low in classic, but high in pleomorphic lobular cancers, which also frequently showed stromal HIF-1 alpha expression. NOTCH1 pathway activation was prognostically unfavorable. In breast cancer, NOTCH pathway activation appears to be associated with a poor prognosis, but NOTCH and HIF signaling do not seem to be functionally associated.