Selective spatial upregulation of intratumoral stromal aromatase in breast cancer patients: evidence for imbalance of local estrogen metabolism

Abstract

The suppression of local estrogens levels is of key importance in the treatment of ER-positive breast cancer. Essentially all endocrine strategies act by either suppressing estrogen formation or competitively inhibiting receptor-binding in tumor cells. Nevertheless, little is still known about the local expression of aromatase and sulfotransferase which are the key modulators of intra-tumoral estrogen levels. We have performed immunohistochemostry to investigate the expression of aromatase and sulfotransferase in 42 samples obtained directly from malignant breast tumors, and compared it to biopsies obtained from uninvolved tissue in the vicinity of the invasion front, and to distant breast tissue. We found that aromatase was equally detectable in both tumor epithelial and stroma, but was mostly epithelial in non-malignant tissues (PZ0.00008, Fisher's exact test). Also, aromatase protein expression was significantly more common in tumoral stroma when compared with peritumoral and distant breast stroma (PZ0.00005, and P!0.00001 respectively). With the notable exception of cystosarcoma phylloides, sulfotransferase protein was detectable only in epithelial tissues, regardless of the location within the diseased breast. However, epithelial sulfotransferase was correlated with epithelial aromatase (rZ0.35461, PZ 0.0009, Spearman's r test) and with the epithelial ER status (rZ0.29313, PZ0.005). We have demonstrated a differential aromatase and sulfotransferase protein expression pattern that is dependent on the spatial relation to a malignant breast tumor. Our results indicate a net increase in intratumoral active estrogen levels through increased stromal aromatization, while physiological local inactivation by sulfotransferase activity remains essentially unchanged.

In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients

“…This hypothesis is partly supported by our observation that ER-positive patients with tumours coexpressing PgR had prolonged RFS compared to those lacking PgR, because PgR is induced by oestrogens at the transcriptional level and is recognised to be associated with a better prognosis and treatment response. When using immunohistochemistry on tumour specimen's aromatase expression was found both in the stroma and in tumour epithelial cells, which is in agreement with what others have seen [29,[38][39][40][41][42]. Interestingly, we found that protein expression of stromal but not cancer epithelial aromatase was related to breast cancer prognosis.…”

Immunohistochemical expression of aromatase and estrogen, androgen and progesterone receptors in normal and neoplastic human meningeal cells

“…Regarding tumors, the presence of aromatase has already been described in breast cancer cells, 1,25,26 as well as in endometrial, 2,27 uterine cervix, 28 ovarian, 3 prolactinsecreting and plurihormonal pituitary adenomas, 29 and in non-small cell lung cancer. 30 Similar to our statement on normal meninges, to date, there are no data in the literature on aromatase expression in meningiomas, which demonstrated negative in the present series.…”

Expression of aromatase and estrogen sulfotransferase in preinvasive and invasive breast cancer

“…The anti-aromatase antibody (dilution 1:1,000 in PBS/Tween) was generated from a rabbit immunoglobin fraction of an antiserum prepared against human placental aromatase and was kindly provided and validated by Dr N Harada (Fujita Health University Hospital, Toyaoake, Japan) (Sasano et al 1994(Sasano et al , 1996. The monoclonal mouse EST Ab1 antibody (EST.1) was purchased from NeoMarkers (Fremont, CA, USA) and was used at a concentration of 2 g/ml with subsequent boiling of tissue sections in 10 mM citrate buVer at pH 6.0 for 15 min as previously described (Singer et al 2006). All slides were incubated overnight at 4°C, followed by a PBS wash for 5 min.…”