In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics

Abstract

Background: The majority of breast cancer cases are steroid dependent neoplasms, with hormonal manipulation of either CYP19/aromatase or oestrogen receptor alpha axis being the most common therapy. Alternate pathways of steroid actions are documented, but their interconnections and correlations to BC subtypes and clinical outcome could be further explored.

Methods: We evaluated selected steroid receptors (Androgen Receptor, Oestrogen Receptor alpha and Beta, Glucocorticoid Receptor) and oestrogen pathways (steroid sulfatase (STS), 17β-hydroxysteroid dehydrogenase 2 (17βHSD2) and aromatase) in a cohort of 139 BC cases from Norway. Using logistic and cox regression analysis, we examined interactions between these and clinical outcomes such as distant metastasis, local relapse and survival.

Results: Our principal finding is an impact of STS expression on the risk for distant metastasis (p<0.001) and local relapses (p <0.001), HER2 subtype (p<0.015), and survival (p<0.001). The suggestion of a beneficial effect of alternative oestrogen synthesis pathways was strengthened by inverted, but non-significant findings for 17βHSD2.

Conclusions: Increased intratumoural metabolism of oestrogens through STS is associated with significantly lower incidence of relapse and/or distant metastasis and correspondingly improved prognosis. The enrichment of STS in the HER2 overexpressing subtype is intriguing, especially given the possible role of HER-2 over-expression in endocrine resistance.

Fig. 1

Overview of the steroidogenic pathways thought to be functional in the breast. The classical steroid receptors thought to govern breast cancer prognosis are the oestrogen receptor alpha (ERα) and the Progesterone Receptor (PR). In addition to these the Human Epidermal Growth Factor Receptor 2 (HER2)is also part of the classical panel used to asses breast cancers. This figure demonstrate the extended endocrine environment of the breast with pathways considered in this paper in black, and additional important and potential pathways not studied in grey. This figure is not intended to be a comprehensive diagram of all possible intracrine pathways present in the breast but a guide to the reader of this paper to help orientate them to the significance of the various proteins examined. Circulating precursors such as DHEA-S and E1-S are found in high concentrations in the circulation as are smaller levels of more active steroids such as oestrone (E1), estradiol (E2), Androstenedione (A) and testosterone and cortisol (not shown). Through a series of enzymatic conversions these steroids can be modulated to have greater or lesser activity on a variety of nuclear receptors such as the androgen receptor (AR), oestrogen receptor beta (ERβ) and glucocorticoid receptor (GR) in addition to the classical hormone receptors. Beyond the actions of nuclear receptors the role of cofactors such as FOXA1 and their interactions with hormone receptors are thought to be central to understanding this complex network of interactions

Fig. 2

Representative IHC images of immunohistochemical stains in breast cancer samples. For each stain we chose the maximal, median and minimal values of the stain and have shown the representative images (×200 magnification). Note in most cases the epithelial location of the staining. While not illustrated here is should be noted that over and entire section of cancer tissue some of these stains were heterogeneous thus the possibility of steroid expressing subpopulations within the one tumour should not be ruled out. At present however there are few scoring approaches to adequately asses this issue and as such it is not dealt with in this manuscript

Fig. 3

The impact of steroidogenic proteins on overall survival. We detected an effect of STS (a), 17βHSD2 (b), and GR (c) expression on overall survival rates with high levels of STS being associated with longer survival while high levels of 17βHSD2 and GR were associated with shorter survival. Survival analysis examining the interactions of STS expression with breast cancer subtype (d) and endocrine therapy (e) revealed that the survival benefit associated with STS expression was not confined to one breast cancer subtype or related to a specific endocrine intervention