Oestrogen producing enzymes and mammary carcinogenesis: a review

Abstract

There is a large and compelling body of epidemiological and experimental evidence that oestrogens are instrumental in the aetiology of breast cancer. Their mechanisms of action are varied, including stimulation of cellular proliferation through receptor-mediated hormonal activity, increasing genetic mutation rates through cytochrome P450-mediated metabolic activation, and induction of aneuploidy. The local biosynthesis of oestrogens especially in postmenopausal women is believed to play a very important role in the pathogenesis and development of hormone dependent breast carcinoma and the over-expression of regulatory enzymes seems to be associated with the development of a more aggressive disease and associated with poor outcome and increased local and distant recurrences. In this article we highlight the role of CYP19 gene expression and aromatase activity in mammary carcinogenesis. Other oestrogen producing (17-beta-hydroxysteroid dehydrogenase and steroid sulphatase) and catalyzing enzymes (3-beta-hydroxysteroid dehydrogenase, Oestrogen sulfotransferase, CYP1A1, CYP1B1, and CYP3A4) are also discussed in some detail. Understanding the mechanisms that regulate these enzymes is crucial to the development of new endocrine therapies in post-menopausal females with hormone dependant breast cancer. Currently, third generation aromatase inhibitors has revolutionized the treatment of oestrogen dependant breast cancer. However, the important role of both STS and 17-beta-HSD type 1 in local oestrogen production provides novel potential targets for endocrine therapy. Such endocrine therapy is currently being explored and the development of STS inhibitors, combined aromatase/steroid sulfatase inhibitors and 17-beta-HSD type 1 inhibitors is underway with promising initial results.

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

“…It is also well established that steroid sulfo-transferases, which convert biologically active estrogens into their inactive sulfates, are also present in breast cancer tissues (Falany & Falany 1996). Therefore, therapeutic targets for breast cancers include not only the binding of estrogen to ER but also the activity of estrogenic enzymes in the tumor tissues (Pasqualini 2004, Sasano et al 2006, Subramanian et al 2008.…”

The interaction between aromatase, metalloproteinase 2,9 and cd44 in breast cancer

“…It is found in women of reproductive age and also in post-menopausal 1,3 . The great difference between these two phases of life is that in postmenopausal women extra-ovarian aromatase plays a fundamental role in the estrogen synthesis (7,12) . The peripheral conversion of androgens to estrogens occurs in the adipose tissue, muscle, skin and also in the breast tissue itself and especially in the latter, significant enhancement of conversion due to higher levels of aromatase expression is associated with malignant changes 10,35,36 .…”

“…Aromatase is a cytochrome P-450 family coded by the CYP19 gene that catalyses the conversion of androstenedione into oestrone (E1) and testosterone into E2 through hydroxylation, oxidation and removes the C-19 carbon and aromatization of the steroid A ring 6,7 . This estrogen synthesis, which is the main form of estrogen production in postmenopausal women, can occur in peripheral tissues, but is found mainly in the local mammary tissue 7 . A large number of studies have shown that local production of estrogen in breast cancer tissue is higher than in normal breast counterparts due to the presence of very high levels of aromatase 8 -12 .…”

Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats

“…13 More importantly, women with elevated estrogen levels are considered to be a high-risk group for breast cancer development 14,15 and are likely to be exposed to diagnostic radiation procedures more frequently. Similarly, many patients with estrogen-induced breast cancer undergo radiation treatment and are exposed to relatively high X-ray doses to the healthy breast.…”