Effects of the MHC on hormonal induction of mammary tumors and function of hypophyseal isografts in the mouse

Abstract

While the role of the H-2 complex in the resistance to virally induced tumors has been extensively studied, little is known about its influence on the development of epithelial tumors of non-viral etiology, although such tumors are most prevalent in humans. Therefore, we analyzed the role of the H-2 complex in susceptibility to mammary tumors induced by hormonal stimulation from heterotopic hypophyseal isografts in H-2 congenic strains from C57BL/10, BALB/c, and O20/A backgrounds. This method of induction allows an assessment of the effect of H-2 genes on the function of various organs involved in this process. We found that the tumor susceptibility genes map to two segments: I-E-S, and to the right of S. The mechanisms by which the H-2 complex affects the induction of mammary tumors in C57BL/10 congenic strains seem to include an influence on several factors involved in the hormonal stimulation, because the susceptible B10 congenic strains have higher plasma levels of prolactin and the H-2 complex also affects the growth of hypophyseal isografts. Their size correlates with tumor development in individual mice in the resistant C57BL/10 congenic strains. We reported previously H-2-dependent differences in levels of the estrogen receptor in hypophysis. For this study, we measured the levels of estrogen receptors in uteri to asses the tissue specificity of this effect of H-2. However, no influence of the H-2 complex on estrogen receptor levels was observed in uteri. Strains from BALB/c and O20 backgrounds developed mammary tumors much earlier than the B10 congenic strains, indicating a strong influence of non-H-2 genes.

What hasGWASdone forHLAand disease associations?

“…Cancer susceptibility is historically linked to the histocompatibility loci. The earliest disease susceptibility study in animals examining MHC effects highlighted its role in leukaemia in mice (Lilly, Boyse, & Old, 1964) followed by other cancers (Oomen, Van der Valk, & Den Engelse, 1983) including breast (Dux & Demant, 1987;Muhlbock & Dux, 1974;Ropcke, Moen, Hart, & Demant, 1990) and lung cancer (Demant, Oomen, & Oudshoorn-Snoek, 1989;Oomen et al, 1983;Snoek et al, 2000). Those studies were not limited to virally induced leukaemia and mammary tumours, but also examined spontaneous, chemically and hormonally induced tumours.…”

VARS2 V552V variant as prognostic marker in patients with early breast cancer

“…Another possible mechanism is immunologic alterations, as supported by studies showing the MHC-controlled induction of mammary tumors in a mouse model [15,16]. Moreover, many cancers and autoimmune diseases are known to be linked to allelic differences in effector proteins, such as Vars2 (G7a), G7b, G7c, and Hsp70 in MHC class III [17][18][19][20][21].…”