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

• Published in: Breast cancer research and treatment Vol. 161; no. 2; pp. 213 - 227
• Main Authors: McNamara, Keely May, Oguro, Saki, Omata, Fumiya, Kikuchi, Kyoko, Guestini, Fouzia, Suzuki, Koyu, Yang, Yang, Abe, Eriko, Hirakawa, Hisashi, Brown, Kristy A., Takanori, Ishida, Ohuchi, Noriaki, Sasano, Hironobu
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.01.2017; Springer; Springer Nature B.V
• Subjects: Analysis; Androgens; Androgens - metabolism; Biomarkers; Breast cancer; Cancer research; Cancer therapies; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Ductal, Breast - pathology; Cell Line, Tumor; Estrogen Receptor beta - metabolism; Estrogens; Estrogens - metabolism; Evaluation; Female; Humans; Immunohistochemistry; Medical schools; Medicine; Medicine & Public Health; Metabolic Networks and Pathways; Metabolism; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Oncology; Oxidoreductases; Phenols (Class of compounds); Physiological aspects; Preclinical Study; Prognosis; Signal Transduction; Steroids; Steroids - metabolism; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - mortality; Triple Negative Breast Neoplasms - pathology; Steroid metabolism; Androgens; Breast cancer; TNBC; Estrogen receptor beta; Estrogens
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-016-4050-2

Purpose While triple-negative breast cancer (TNBC) is negative for estrogen receptor alpha, a substantial proportion of carcinomas express estrogen receptor beta (ERβ); consequently, estrogen actions and metabolism may be relevant in this cancer subtype. Methods 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. Results 17βHSD2 was detected in the highest number of cases followed by 17βHSD1, 17βHSD6 and aromatase. When comparing the expression of ERβ with that of the enzymes, it was positively correlated with the expression of 17βHSD6 ( p  < 0.05) and trended towards correlation with dual expression of 17βHSD1 and 2 ( p  < 0.07). 17βHSD1 was associated with significantly reduced tumour volume ( p  = 0.0025), while ERβ was associated with a trend towards reduced lymphovascular invasion, ( p  < 0.061). Interestingly, in survival analysis, 17βHSD6 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 17βHSD6 ( 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 ERβ in a subset of AR expressing TNBC cell lines (MDA-MB-453, SUM-185-PE and MFM-223). Conclusion Overall this study suggests the presence of, and a potential protective effect of estrogens in TNBC.