Male breast cancer (MBC) occurs at less than 1% frequency of female breast cancer, and its actual etiology is still unclear. We hypothesize that males are protected from contracting breast cancer because the male-specific region of the human Y chromosome (MSY) has breast tumor suppressive function. Here, we show via fluorescence in situ hybridization (FISH) and droplet digital PCR (ddPCR) that Y chromosome was lost clonally at a frequency of ~15% (5/32) in two independently collated cohorts of MBC patients. We also show via FISH that this clonal Y loss occurred since ductal carcinoma in situ (DCIS) stage of MBC. Furthermore, we investigated regional loss of the Y chromosome in MBC patients who retained their Y chromosomes with STS-PCR (sequence-tagged-site PCR), derived from the male specific region of the Y chromosome Breakpoint Mapper (MSY-BPM), and showed nullisomic loss of TMSB4Y in a MBC patient. We showed via immunohistochemistry (IHC) that TMSB4Y is expressed in normal male breast tissue. Dox inducible cell lines of TMSB4Y, TmY1 and TmY2, were generated in the female breast epithelial cell line MCF-10A background. Dox-induced expression of TMSB4Y resulted in altered morphology and reduced cell proliferation. Furthermore, reverse phase protein array (RPPA) analysis on TmY1 showed reduced expression of Syk (spleen tyrosine kinase) after Dox-induced expression of TMSB4Y. Interestingly, though TMSB4Y is highly homologous to its homologue TMSB4X on the X chromosome, the TMSB4Y antibody is solely specific to TMSB4Y, which suggests differences between TMSB4Y and TMSB4X. Taken together, our results suggest that in situ clonal loss of human Y chromosome might contribute to MBC tumorigenesis, and that TMSB4Y is tumor suppressive through regulating breast cell morphology and reducing cell proliferation.
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