CD34 is a transmembrane glycoprotein that is thought to be involved in the modulation of cell adhesion and signal transduction,28
and is expressed by mesenchymal cells at several sites, including the normal mammary stroma.30,33
Loss of CD34 by mesenchymal cells has been described in several situations where there is malignant transformation of the mesenchymal population. Malignant phyllodes tumours of the breast exhibit lower levels of CD34 expression than benign phyllodes or fibroadenomas,24,33,35
and CD34 is lost in sarcomas arising within CD34 positive dermatofibrosarcoma protruberans.36
Loss of fibroblast CD34 has also been described in non-neoplastic fibroblasts around epithelial tumours, such as basal cell carcinoma37
and colorectal carcinoma.38
“Loss of CD34 may be related to invasive potential”
Our study has shown that fibroblast CD34 expression is consistently lost in invasive breast carcinomas that include microinvasion, and in a high proportion of cases of DCIS, particularly high grade lesions, which are thought to be more likely to progress to invasion.39
Loss of expression is also seen in a proportion of ADH, but not around glandular structures showing LCIS. This is of interest because ADH and DCIS are regarded as premalignant lesions, whereas LCIS is considered to confer an increased risk of developing carcinoma, but the risk relates to the development of carcinoma in either breast, not to the site of the LCIS.40
This raises the possibility that loss of CD34 may be related to invasive potential. The change in CD34 expression is very localised, with loss around a duct containing DCIS, but retained expression around adjacent normal breast glands, and this strongly implicates epithelial–mesenchymal interactions in the control of expression, as has been suggested previously in the case of phyllodes tumours.33
What determines the loss of CD34 is of interest because not all DCIS cases show loss, and this may point to different functional states of the neoplastic epithelium, which are important in determining their invasive potential. However, whereas it has previously been suggested that the loss of CD34 is specific to malignancy,41
we show that this is not the case. Although most benign lesions, including HUT, retain CD34 expression, loss of CD34 was a consistent finding in the fibroblasts associated with areas of fibrosis following core biopsy and in radial scars; in this last case, whether they were associated with malignancy or not. Although on the surface this makes CD34 less valuable as a diagnostic marker of malignancy—particularly in sclerotic lesions—it raises interesting questions as to the state of differentiation of fibroblasts in different breast lesions, and the potential relevance of this in terms of fibroblast function. Some studies suggest that radial scars are associated with an increased risk of development of malignancy,42
and several other studies have shown similar alteration in the stroma of radial scars as seen in invasive carcinomas, such as increased hyaluronic acid43
and increased expression of ED-A fibronectin and vascular endothelial growth factor.44
The importance of loss of expression of CD34 on stromal cells in reactive fibrosis is unclear, although it could possibly be related to the terminal differentiation of these cells.
Take home messages
- Smooth muscle actin positive myofibroblasts express CD34 to varying degrees, indicating that these markers are not coordinately controlled
- The loss of CD34 is strongly related to the malignant phenotype, in both invasive and preinvasive disease, but is not entirely specific because radial scar fibroblasts and fibroblasts in reactive fibrosis exhibit a similar phenotype
- The functional relevance of altered CD34 expression is unclear but the very focal changes implicate local signalling mechanisms, probably epithelial in origin
- In vitro studies should be undertaken to establish the role of CD34 in the breast fibroblast
“It is essential that the changes in fibroblast phenotype associated with malignancy are carefully dissected, not only to validate their use as possible diagnostic markers, but also to establish their potential as therapeutic targets”
The importance of changes in fibroblast function in promoting tumour progression is increasingly recognised and such a tumour promoting effect is frequently attributed to the activation of fibroblasts to αSMA positive myofibroblasts. However, our study clearly demonstrates that acquisition of the myofibroblast phenotype is not indicative of malignancy in the breast, and it also demonstrates that not all myofibroblasts have the same phenotype, some being CD34 positive, as in fibroadenomas, and others being CD34 negative, as in invasive and many in situ lesions. The potential for the stromal response to tumours becoming a target for treatment is increasing, with clinical trials in place for fibroblast derived factors such as MMP45
However, it is essential that the changes in fibroblast phenotype associated with malignancy are carefully dissected, not only to validate their use as possible diagnostic markers, but also to establish their potential as therapeutic targets.
The functional relevance of fibroblast CD34 expression and its loss is not clear, although it may represent a change from a multipotent mesenchymal cell to a committed cell type. However, the variable association between CD34 and αSMA expression demonstrates that not all myofibroblasts are the same, and that the loss of CD34 appears to be more closely related, although clearly not specific, to malignancy than the acquisition of αSMA. This suggests that αSMA may not be the most important marker of fibroblast function, and in vitro studies are now indicated to establish the role of CD34 in the breast fibroblast.