Autocrine Prolactin Stimulates Endometrial Carcinoma Growth and Metastasis and Reduces Sensitivity to Chemotherapy.

Abstract

Advanced and recurrent endometrial carcinoma (EC) exhibits a poor response to chemotherapy and low survival rates. It has been previously reported that human prolactin (hPRL) is upregulated in endometrial cancer and is associated with worse survival outcomes. We provide evidence for the functional role of hPRL in EC progression. We generated a model for the study of autocrine hPRL-mediated cell functional effects through the forced expression of hPRL in human EC cells. Autocrine hPRL expression stimulated cell proliferation, anchorage-independent growth, migration, and invasion of EC cells and promoted tumor growth, local invasion, and metastatic colonization in xenograft models. In addition, forced expression of hPRL decreased sensitivity of EC cells to chemotherapeutic drugs (i.e., doxorubicin and paclitaxel), both in vitro and in vivo. Consistently, small interfering RNA-mediated depletion of hPRL significantly reduced oncogenicity and enhanced the chemosensitivity of EC cells. As CD24 is hPRL-regulated and has been implicated in drug resistance in EC, we further showed that CD24 is a critical mediator of hPRL-stimulated reduced sensitivity to doxorubicin and paclitaxel in EC cells. Therefore, inhibition of hPRL signaling is a potential therapeutic strategy for the treatment of late-stage EC, which can be used in combination with chemotherapy to improve the chemotherapeutic response.