High Notch1 protein expression is an early event in breast cancer development and is associated with the HER-2 molecular subtype.
OBJECTIVE
Activation of Notch signalling results in hyperplasia and tumorigenesis in murine mammary epithelium. However, there is little information regarding the expression of Notch1 in premalignant lesions and early breast cancer. We investigated expression of Notch1 in breast cancer development and its association with molecular subtypes.


RESULTS
Immunohistochemical expression of Notch1 was determined in a murine model of mammary carcinogenesis and in breast tissue from two cohorts of breast cancer patients, the first (n=222) comprising a histological progression series and the second an outcome series of 228 patients with operable invasive ductal carcinoma. Enhanced expression of Notch1 protein was an early event in both murine and human breast cancer development with progressive increases in expression with the development of hyperplasia and malignancy. High Notch1 was not prognostic in the outcome cohort. There was, however, a highly significant association of high Notch1 protein with the HER-2 molecular subtype of breast cancer (P=0.008).


CONCLUSIONS
These data demonstrate that aberrant Notch regulation is an early event in mammary carcinogenesis and is associated with the HER-2 molecular subtype of breast cancer, and suggest the Notch signalling pathway may be a potential therapeutic target worthy of further investigation.
Zardawi
Sarah J
SJ
Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, NSW, Australia.
Zardawi
Ibrahim
I
McNeil
Catriona M
CM
Millar
Ewan K A
EK
McLeod
Duncan
D
Morey
Adrienne L
AL
Crea
Paul
P
Murphy
Niamh C
NC
Pinese
Mark
M
Lopez-Knowles
Elena
E
Oakes
Samantha R
SR
Ormandy
Christopher J
CJ
Qiu
Min Ru
MR
Hamilton
Anne
A
Spillane
Andrew
A
Soon Lee
Cheok
C
Sutherland
Robert L
RL
Musgrove
Elizabeth A
EA
O'Toole
Sandra A
SA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D008875:Middle Aged; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis; D055815:Young Adult
D018719:Erb-b2 Receptor Tyrosine Kinases; D051881:Receptor, Notch1; C497761:NOTCH1 protein, human