Volume 3, Issue 2

Sex steroids, particularly estrogen and progesterone, promote normal breast tissue growth and differentiation. Prolonged exposure of estrogen and/or progesterone is considered a risk factor for breast cancer carcinogenesis, and the effects of sex steroids on breast cancer metastasis are controversial. Emerging evidence indicates that sex steroids regulate breast cancer metastatic processes via nongenomic and genomic mechanisms. Through the regulation of actin-binding proteins estrogen and progesterone rapidly provoke actin cytoskeleton reorganization in breast cancer cells, leading to formation of membrane structures facilitating breast cancer cell migration and invasion. In addition, steroid receptors interact and trans-activate receptor tyrosine kinases (including epidermal growth factor receptor and insulin-like growth factor receptor), resulting in growth factor-like effects that promote cancer cell invasive behavior. Moreover, sex steroids regulate the expression of metastasis-associated molecules, such as E-cadherin, matrix metalloproteinases, growth factors, chemokines and their receptors, leading to epithelial-to-mesenchymal-like transition. However, there is also evidence that sex steroids and their receptors protect against breast cancer cell invasiveness through distinct mechanisms. Here, we present an overview of the currently identified actions of sex steroids on breast cancer metastasis and their potential clinical implications.

It has been established that carrying a pregnancy to full-term at an early age can protect against contracting cancer by up to 50% in later life. The trophoblast theory of cancer states that trophoblast and cancer tissue are very similar. New findings suggest that the loss of fetal cells during pregnancy resemble those cells responsible for causing metastasis in cancer. Fetal cells and spreading cancer cells are highly proliferative. They are similar to stem cells, exhibiting no or low hormone receptor expression, and require a hormone receptor independent mechanism for control. Control of membrane stability during pregnancy is of vital importance for a successful pregnancy and is mediated by androstenediol and 2-methoxyestradiol. 2-Methoxyestradiol has no hormone receptor affinity and elicits strong anticancer effects particularly against cancer stem cells and fetal cells, for which currently no treatment has yet been established. There is a discussion whether pregnancy reduces cancer stem cells in the breast. Soy isoflavones are structurally similar to both hormones, and elicit strong anticancer effects and antiangiogenesis via inhibition of NF-κB, even in hormone receptor independent breast cancers seen in epidemiologic studies. The trophoblast theory of cancer could help to explain why soy baby nutrition formulas have no effect on baby physiology, other than the nutritional aspect, although soy elicits many effects on the adult immune system. To survive the immune system of the mother, the immune system of the fetus has to be separated; otherwise, the reduction of the immune system in the mother, a necessary feature for the blastocyst to grow, would immediately reduce the immunity for the fetus and endanger its survival. Similar to a fetus, newly born babies show immune insensitive to Th1 and Th2 cytokines, which are necessary and crucial for regulating the immune system of the mother, thus raising the risk of the baby of developing allergies and neurodermatitis. Gene expression studies in vitro as well as in circulating tumor cells from patients consuming a fermented soy product support the antiangiogenic as well as antiproliferative effects of soy.

Intratumoral biosynthesis of sex steroids is thought to play a role in the pathogenesis and development of human breast cancer. There is evidence that androgens can inhibit the development and progression of breast cancer. Among the enzymes involved in the biosynthesis of androgens, 5α-reductase plays a key role by reducing testosterone to dihydrotestosterone, the most potent androgen. Two isoforms of 5α-reductase have been characterized and 5α-reductase type 1 is predominant in breast cancer tissue. We developed specific antibodies to 5α-reductase type 1 and studied the expression of the enzyme in 84 specimens of breast carcinoma and adjacent non-malignant tissues by immunohistochemistry. The results were correlated with the expression of androgen receptor, estrogen receptor α, progesterone receptor and CDC47, a cell division marker as well as the tumor stage, tumor size, nodal status and menopausal status. The expression of 5α-reductase type 1 in 61% of breast cancer specimens appeared significantly lower than that observed in normal adjacent tissues (87% of cases being positive). There was no significant correlation between 5α-reductase type 1 expression and the clinicopathological parameters studied. The decrease in 5α-reductase type 1 expression in breast cancer as compared to that observed in the adjacent normal tissues could play a role in the development and/or progression of the cancer by modifying the intratumoral levels of androgens.

Background : The progestogen nomegestrol acetate (NOMAC), a 17α-hydroxy-nor-progesterone derivative (LUTENYL ® ) is largely used as an oral contraceptive and to treat menopausal complaints. In previous studies, we demonstrated that NOMAC is an anti-sulfatase agent in MCF-7 and T-47D breast cancer cells. In this study, we explore the effect of NOMAC on aromatase activity in a stable aromatase-expressing human breast cancer cell line: MCF-7aro. Materials and methods : Cells were incubated with physiological concentrations of androgen substrates [ 3 H]-testosterone or [ 3 H]-androstenedione (5×10 –9  mol/L) alone, or in the presence of NOMAC (5×10 –5  mol/L–5×10 –8  mol/L) for 24 h at 37°C. [ 3 H]-Estradiol (E 2 ), [ 3 H]-estrone (E 1 ), [ 3 H]-testosterone and [ 3 H]-androstenedione were characterized by thin layer chromatography and quantified using the corresponding standard. Results : Aromatase activity levels are high in MCF-7aro cells because the [ 3 H]-E 2 concentration after incubation of [ 3 H]-testosterone was 5.8±0.31 pmol/mg DNA in non-treated cells. At concentrations of 5×10 –5  mol/L, 5×10 –6  mol/L and 5×10 –7  mol/L NOMAC significantly inhibits this conversion by 49.7%, 29.9% and 18.1%, respectively. After [ 3 H]-androstenedione incubation, similar inhibition levels were observed with NOMAC for [ 3 H]-E 1 formation; whereas, inhibition of [ 3 H]-E 2 production, which implicates 17β-hydroxysteroid dehydrogenase activity in this pathway, is greater because NOMAC also inhibits this enzyme. Conclusion : The MCF-7aro cell line shows high aromatase activity and NOMAC can act as an anti-aromatase agent by inhibiting this activity. This is an important new effect of this progestogen. Because NOMAC can also inhibit sulfatase activity in breast cancer cells, we suggest that this dual effect of NOMAC has attractive possibilities for clinical trials.