TY - JOUR
T1 - HIF-1a and NOTCH signaling in ductal and lobular carcinomas of the breast
AU - Ercan, Cigdem
AU - Vermeulen, Jeroen F.
AU - Hoefnagel, Laurien
AU - Bult, Peter
AU - Van Der Groep, Petra
AU - Van Der Wall, Elsken
AU - van Diest, Paulus Joannes
PY - 2012/12
Y1 - 2012/12
N2 - Background 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-1a 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. Methods Since the link between HIF-1a and NOTCH signalling has hardly been studied, we set out to closely investigate associations between the expression of HIF-1a and NOTCH pathway members in primary and metastatic human breast cancer specimens and their prognostic value. Results Co-expression of NOTCH1 intracellular domain (N1ICD) and HIF-1a was associated with a high grade and a high proliferation rate in invasive breast cancer. HIF- 1a expression was low in classic, but high in pleomorphic lobular cancers, which also frequently showed stromal HIF- 1a expression. NOTCH1 pathway activation was prognostically unfavorable. Conclusion 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.
AB - Background 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-1a 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. Methods Since the link between HIF-1a and NOTCH signalling has hardly been studied, we set out to closely investigate associations between the expression of HIF-1a and NOTCH pathway members in primary and metastatic human breast cancer specimens and their prognostic value. Results Co-expression of NOTCH1 intracellular domain (N1ICD) and HIF-1a was associated with a high grade and a high proliferation rate in invasive breast cancer. HIF- 1a expression was low in classic, but high in pleomorphic lobular cancers, which also frequently showed stromal HIF- 1a expression. NOTCH1 pathway activation was prognostically unfavorable. Conclusion 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.
KW - Breast cancer
KW - Hypoxia inducible factor-1
KW - Metastasis
KW - NOTCHsignaling
KW - Prognosis
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U2 - 10.1007/s13402-012-0102-8
DO - 10.1007/s13402-012-0102-8
M3 - Article
C2 - 23008060
AN - SCOPUS:84879237688
SN - 2211-3428
VL - 35
SP - 435
EP - 442
JO - Cellular Oncology
JF - Cellular Oncology
IS - 6
ER -