title: The presence and impact of estrogen metabolism on the biology of triple-negative breast cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  Overall this study suggests the presence of, and a potential protective effect of estrogens in TNBC.
authors.affiliation: Department of Anatomical Pathology and Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan. kmcnamara@patholo2.med.tohoku.ac.jp.
authors.forename: Keely May
authors.initials: KM
authors.lastname: McNamara
authors.affiliation: Department of Anatomical Pathology and Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Oguro
authors.affiliation: Department of Anatomical Pathology and Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Omata
authors.affiliation: Department of Anatomical Pathology and Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Department of Anatomical Pathology and Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Fouzia
authors.initials: F
authors.lastname: Guestini
authors.affiliation: Departments of Pathology and Surgery, St Lukes Hospital, Tokyo, Japan.
authors.forename: Koyu
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Departments of Pathology and Surgery, St Lukes Hospital, Tokyo, Japan.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Departments of Pathology and Surgery, St Lukes Hospital, Tokyo, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Abe
authors.affiliation: Department of Pathology, Tohoku Kosai Hospital, Sendai, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hirakawa
authors.affiliation: Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Brown
authors.affiliation: Department of Anatomical Pathology and Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Ishida
authors.initials: I
authors.lastname: Takanori
authors.affiliation: Department of Anatomical Pathology and Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Ohuchi
authors.affiliation: Department of Anatomical Pathology and Surgery, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
mesh_terms: D000728:Androgens / Q000378:metabolism; D015415:Biomarkers; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D015398:Signal Transduction; D013256:Steroids / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
chemical_list: D000728:Androgens; D015415:Biomarkers; D047629:Estrogen Receptor beta; D004967:Estrogens; D013256:Steroids
keywords: Androgens; Breast cancer; Estrogen receptor beta; Estrogens; Steroid metabolism; TNBC