Absence of the steroid receptor coactivator-3 induces B-cell lymphoma

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Abstract
Steroid receptor coactivator 3 (SRC‐3/ACTR/AIB‐1/pCIP/RAC3/TRAM‐1) is a member of the p160 family of nuclear receptor coactivators that plays an important role in mammary gland growth, development, and tumorigenesis. We show that deletion of SRC‐3 gene decreases platelet and increases lymphocytes numbers, leading to the development of malignant B‐cell lymphomas upon aging. The expansion of the lymphoid lineage in SRC‐3−/− mice is cell autonomous, correlates with an induction of proliferative and antiapoptotic genes secondary to constitutive NF‐κB activation, and can be reversed by restoration of SRC‐3 expression. NF‐κB activation is explained by the degradation of IκB, consequent to increases in free IκB kinase, which is no longer inhibited by SRC‐3. These results demonstrate that SRC‐3 regulates lymphopoiesis and in combination with previous studies indicate that SRC‐3 has vastly diverging effects on cell proliferation depending on the cellular context, ranging from proliferative and tumorigenic (breast) to antiproliferative (lymphoid cells) effects.