Carcinogenesis, Vol 19, 1437-1444, Copyright © 1998 by Oxford University Press
SE Eltom, MC Larsen and CR Jefcoate
The expression of CYP1B1 in human mammary fibroblasts (HMFs) was
characterized as a potential modulator of their individual function as well
as effects on adjacent mammary epithelia. We have used these
characteristics to explore the diversity of fibroblast cells isolated from
reduction mammoplasty patients and from different breast locations in
breast cancer patients (tumors, peripheral to tumor and skin). These
parameters have also been used to examine differences between two donors.
The results have shown that while none of these HMFs expressed a detectable
CYP1A1 protein basally or in response to TCDD, they all expressed CYP1B1
constitutively at similar levels (0.5-0.9 pmol/mg microsomal proteins) and
they were induced by TCDD (up to 5-fold) consistent with mediation by the
Ah receptor (AhR). DMBA metabolism by HMFs exhibited high proportions of
5,6-, 10,11- and 3,4-dihydrodiols, a profile that is typical of human
CYP1B1 regioselectivity. RT-PCR followed by Southern blot analyses
demonstrated that CYP1B1 mRNA expression in HMFs parallels levels of
respective microsomal proteins. The AhR is expressed in these HMFs as two
cytosolic forms (approximately 106 and 104 kDa) and a substantial
proportion of the 104 kDa form was localized to the nucleus even prior to
TCDD treatment. In all HMFs isolated directly from collagenase digested
breast tissues the AhR is expressed at levels 10-fold lower than in breast
epithelial cells. However, HMFs that were isolated after serial passaging
of mammary epithelial cultures had shown much higher levels of the AhR
expression and more dramatic TCDD-induced down-regulation (>80% in 24 h)
associated with more efficient nuclear translocation. These differences
suggested the presence of two functionally distinct subtypes of HMFs:
interstitial stromal fibroblasts that are readily released by collagenase
digestion of breast tissues, and lobular stromal fibroblasts which are more
tightly associated with the breast epithelia.
ARTICLES
Expression of CYP1B1 but not CYP1A1 by primary cultured human mammary stromal fibroblasts constitutively and in response to dioxin exposure: role of the Ah receptor
Environmental Toxicology Center and The Department of Pharmacology, University of Wisconsin, Madison 53706, USA.
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