Abstract
Most lymphomas show higher incidence and poorer prognosis in males compared to females. However, the endocrine contribution to this gender difference is not entirely known. Here we show that castration accelerates lymphoma growth in C57BL6 male mice grafted with murine EG7 T cell lymphoma cells. However, the androgen receptor antagonist Bicalutamide did not affect lymphoma growth, suggesting no impact of androgen receptor signaling on lymphoma progression. In contrast, inhibition of androgen-to-estrogen conversion by the aromatase inhibitor (AI) Letrozole induced faster lymphoma growth in mice, suggesting that androgens impact lymphoma growth through its conversion to estrogens. This was supported by the inability of dihydrotestosterone, which is not converted to estrogens by aromatase, to influence lymphoma growth in castrated male mice. Lymphoma growth was also stimulated in immunocompromised mice grafted with human B cell lymphoma (Granta-519) and treated with either reversible or irreversible AIs, showing that the blockage of estrogen synthesis caused enhanced growth of both murine T and human B cell lymphomas and with different AIs. Additionally, AI-treated EG7 lymphomas showed accelerated growth not only in male but also in intact female mice. Altogether, our results demonstrate that aromatase inhibition accelerates lymphoma growth but not androgens per se, highlighting a protective role of estrogens in lymphoma pathogenesis. These results also raise concern that the use of AIs in women with breast cancer might enhance lymphoma progression.
Highlights
Most lymphomas, Non-Hodgkin lymphomas (NHL), show a higher incidence and poorer prognosis in males than in females [1, 2]
Since androgens can be converted to estrogens by aromatase, we studied whether androgens had a direct effect on lymphoma growth or if it was mediated through conversion to estrogens
At the end of the experiment, tumors removed from castrated mice had a significantly larger weight compared to sham-operated tumors (Figure 1B) and exhibited a higher number of proliferating tumor cells as assessed by Ki67 staining (Figure 1C)
Summary
Non-Hodgkin lymphomas (NHL), show a higher incidence and poorer prognosis in males than in females [1, 2]. As an explanation behind this gender difference, high estrogen levels have been suggested to protect against lymphomas in women, at reproductive age [3]. In Diffuse Large B Cell Lymphoma, the most common lymphoma type, a gender difference is seen in incidence between pre-menopausal women and men but not between post-menopausal women and men [2, 4, 5]. Several epidemiological data suggest that NHL may be estrogen-regulated. Estrogen action in their target tissue is largely mediated through two nuclear receptors, namely estrogen receptor α (ERα) and ERβ [10, 11]. The main ER expressed in both normal lymphocytes as well in lymphoma cells is ERβ while ERα levels are very low or undetectable [14,15,16]
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