| Popis: |
In response to estrogens, estrogen receptor alpha (ERα) is degraded by the 26S proteasome; however, despite the continued presence of estrogen prior to menopause, ERα protein levels are maintained by an unidentified mechanism. We find that the Ser/Thr kinase, RSK2, negatively regulates ERK1/2-dependent ERα degradation in the mammary gland to maintain ERα protein levels in cycling adult female mice. In RSK2 knockout (RSK2-KO) mice, ERα protein levels are decreased ~70% in the adult mammary gland compared to the control. Mammary gland regeneration experiments demonstrated that regulation of ERα protein levels by RSK2 is intrinsic to the mammary epithelium. In juvenile animals the ERK1/2-RSK2 pathway is not active and consistent with that observation the ERα protein levels are similar in juvenile wild type and RSK2-KO mice. In adults, the levels of active ERK1/2 increase ~25-fold relative to juvenile mammary glands. Activation of ERK1/2 in the adult is restricted to the estrus phase of the estrous cycle and activation of ERK1/2 is estrogen-dependent. Oophorectomy or inhibition of the 26S proteasome restored ERα protein levels in RSK2-KO mice. Loss of RSK2 results in activation of ERK1/2 throughout the estrous cycle and results in an enrichment for estrogen-responsive genes in the RSK2-KO ER+ mammary epithelial cells relative to wild type. These data support a model in which the unrestricted activation of ERK1/2 in RSK2-KO mice drives inappropriate transcription-coupled proteolysis of ERα which leads to an increase in DNA-double stranded breaks. Bioinformatic analysis demonstrated a correlation between decreased RSK2 expression and increased expression of estrogen-regulated gene in normal breast tissue from women taking oral contraceptives. Furthermore, the RSK2-KO transcriptome signature identified a subset of ER+ breast cancer patients with low RSK2 expression. These findings establish RSK2 as a regulator of estrogen homeostasis in the pre-menopausal adult and suggest a possible mechanism for the increased cancer risk in women taking exogenous estrogens. Funding source: NIH |
