Hormones, receptors, and growth in hyperplastic enlarged lobular units: early potential precursors of breast cancerReport as inadecuate

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Breast Cancer Research

, 8:R6

First Online: 16 December 2005Received: 05 August 2005Revised: 10 November 2005Accepted: 15 November 2005


IntroductionThe hyperplastic enlarged lobular unit HELU is a common alteration in adult female human breast and is the earliest histologically identifiable lesion with premalignant potential. Growth and differentiation in normal epithelium are regulated by estrogen and progesterone, whose effects are mediated through estrogen receptor ER-α and progesterone receptor PR. We assessed correlations between growth proliferation and apoptosis, endogenous hormone levels using age as a surrogate for menopausal-estrogen status, and ER-α-PR expression in HELUs versus adjacent normal terminal duct lobular units TDLUs to gain insight into potentially premalignant hyperplasia.

MethodsProliferation Ki67 antigen, ER-α, and PR were assessed by immunohistochemistry, apoptosis using the TUNEL terminal transferase-mediated dUTP nick end-labeling assay, and nuclear colocalization of ER-α and Ki67 by dual-labeled immunofluorescence in HELUs and adjacent TDLUs n = 100–584, depending on the factor from 324 breasts. All factors were quantified under direct microscopic visualization. ER-α-PR expression was semiquantified by estimating the proportion of positive cells 0 = none, 1 = <1-100, 2 = 1-100 to 1-10, 3 = 1-10 to 1-3, 4 = 1-3 to 2-3, and 5 = >2-3. Ki67, TUNEL, and colocalization of ER-α and Ki67 were scored by absolute counting %positive.

ResultsER-α and PR expression were significantly elevated in HELUs versus adjacent TLDUs average score: 4.5 versus 3.1 and 3.5 versus 2.1; P < 0.0001. Proliferation was also significantly higher in HELUs versus TDLUs average 6.3% versus 2.0%; P < 0.0001. In contrast, apoptosis was significantly lower in HELUs versus TDLUs average 0.61% versus 0.22%; P < 0.0001. Changes in proliferation and receptor expression were similar between premenopausal and postmenopausal TDLUs and HELUs, suggesting that hyperplastic cells remain responsive to regulation by estrogen. The proportion of ER-positive-proliferating cells was much higher in HELUs than TDLUs 27.6% vs. 4.9%; P < .0001.

ConclusionDevelopment of HELUs is associated with increased proliferation and decreased cell death relative to normal cells. ER-α and PR are highly elevated in HELUs, which may contribute to the hyperplasia because they mediate hormonal regulation of growth. An understanding of the fundamental causes of increased levels of receptors and growth may lead to new strategies to prevent breast cancer.

AbbreviationsADHatypical ductal hyperplasia

DCISductal carcinoma in situ

ERestrogen receptor

HELUhyperplastic enlarged lobular unit

IBCinvasive breast cancer

PRprogesterone receptor

TDLUterminal duct lobular unit

TGFtransforming growth factor

TUNELterminal transferase-mediated dUTP nick end-labeling.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr1367 contains supplementary material, which is available to authorized users.

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Author: Sangjun Lee - Syed K Mohsin - Sufeng Mao - Susan G Hilsenbeck - Dan Medina - D Craig Allred

Source: https://link.springer.com/


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