The presence and impact of estrogen metabolism on the biology of triple-negative breast cancer

While triple-negative breast cancer (TNBC) is negative for estrogen receptor alpha, a substantial proportion of carcinomas express estrogen receptor beta (ER beta); consequently, estrogen actions and metabolism may be relevant in this cancer subtype. A cohort of 81 TNBC patients from Tohoku University Hospital, Japan were characterised with regard to the expression of estrogen receptor beta and enzymes known to modulate levels of estrogens in breast and other tissues (Aromatase, 17-beta- Hydroxysteroid dehydrogenases 1, 2 and 6). This was done at the protein level by means of immunohistochemistry. As this cohort has been previously characterised for androgens, this also allows for comparison between the expressions of estrogen-related proteins and of androgen-related proteins. Preliminary mechanistic studies in cell culture were also undertaken. 17 beta HSD2 was detected in the highest number of cases followed by 17 beta HSD1, 17 beta HSD6 and aromatase. When comparing the expression of ER beta with that of the enzymes, it was positively correlated with the expression of 17 beta HSD6 (p < 0.05) and trended towards correlation with dual expression of 17 beta HSD1 and 2 (p < 0.07). 17 beta HSD1 was associated with significantly reduced tumour volume (p = 0.0025), while ER beta was associated with a trend towards reduced lymphovascular invasion, (p < 0.061). Interestingly, in survival analysis, 17 beta HSD6 expression was the only one of these five factors that influenced survival, with positive samples being associated with longer disease-free survival compared to those that were negative for 17 beta HSD6 (p < 0.05). In assessing associations with expression of proteins in the androgenic pathway, expression of aromatase appeared to be associated with androgenic pathways in TNBC patients (p < 0.05). Due to this association and the potential relevance to androgen-directed therapies in TNBC, we evaluated this interaction in vitro. We observed androgen-dependent upregulation of aromatase and ER beta in a subset of AR expressing TNBC cell lines (MDA-MB-453, SUM-185-PE and MFM-223). Overall this study suggests the presence of, and a potential protective effect of estrogens in TNBC.