Characterization of mammary adenocarcinomas in male rats after N-methyl-N-nitrosourea exposure—Potential for human male breast cancer model

• Published in: Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie 2016-05, Vol.68 (5), p.263-270
• Main Authors: Yoshizawa, Katsuhiko, Yuki, Michiko, Kinoshita, Yuichi, Emoto, Yuko, Yuri, Takashi, Shikata, Nobuaki, Elmore, Susan A., Tsubura, Airo
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - chemically induced; Adenocarcinoma - pathology; Animals; Breast cancer; Breast Neoplasms, Male - chemically induced; Breast Neoplasms, Male - pathology; Carcinogens - pharmacology; Disease Models, Animal; Female; Humans; Immunohistochemistry; Male; Male rat; Mammary adenocarcinoma; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - pathology; Mammary Neoplasms, Animal - chemically induced; Mammary Neoplasms, Animal - pathology; Methylnitrosourea - pharmacology; N-methyl-N-nitrosourea; Rats
• ISSN: 0940-2993; 1618-1433
• DOI: 10.1016/j.etp.2016.01.005

The frequency of breast cancer in men is extremely rare, reported to be less than 1% and there is currently no available animal model for male mammary tumors. We compared the characteristics of various immunohistochemical markers in N-methyl-N-nitrosourea (MNU)-induced mammary adenocarcinomas in male and female Crj:CD(SD)IGS rats including: estrogen receptor α (ER), progesterone receptor (PgR), androgen receptor (AR), receptor tyrosine-protein kinase erbB-2 (HER2), GATA binding protein 3 (GATA3), and proliferating cell nuclear antigen (PCNA). Female mammary adenocarcinomas were strongly positive in the nuclei of tumor cells for PCNA and ER (100%) with only 60% and 53% expressing PgR and GATA3, respectively. 100% of male adenocarcinomas also exhibited strongly positive expression in the nuclei of tumor cells for PCNA, with 25% expressing AR and only 8% showing positivity for ER. Male carcinomas did not express PgR or GATA3 and none of the tumors, male or female, were positive for HER2. Based on the observed ER and PgR positivity and HER2 negativity within these tumors, MNU-induced mammary adenocarcinomas in female rats appear to be hormonally dependent, similar to human luminal A type breast cancer. In contrast, MNU-induced mammary adenocarcinomas in male rats showed no reactivity for ER, PgR, HER2 or GATA3, suggesting no hormonal dependency. Both male and female adenocarcinomas showed high proliferating activity by PCNA immunohistochemistry. Based on our literature review, human male breast cancers are mainly dependent on ER and/or PgR, therefore the biological pathogenesis of MNU-induced male mammary cancer in rats may differ from that of male breast cancer in humans.