Study Identifies PKCα as a Key Driver of Estrogen Signaling in Endometrial Cancer
Endometrial cancer is the most common invasive gynecologic malignancy in developed countries. The most prevalent endometrioid tumors are linked to excessive estrogen exposure and hyperplasia. However, the molecular mechanisms and signaling pathways underlying their etiology and pathophysiology remain poorly understood.
Authors have shown that protein kinase C𝛼 (PKC𝛼) is aberrantly expressed in endometrioid tumors and is an important mediator of endometrial cancer cell survival, proliferation, and invasion. In this study, authors demonstrated that expression of active, myristoylated PKC𝛼 conferred ligand-independent activation of estrogen-receptor-(ER-)dependent promoters and enhanced responses to estrogen. Conversely, knockdown of PKC𝛼 reduced ER-dependent gene expression and inhibited estrogen-induced proliferation of endometrial cancer cells.
The ability of PKC𝛼 to potentiate estrogen activation of ER-dependent transcription was attenuated by inhibitors of phosphoinositide 3-kinase (PI3K) and Akt. Evidence suggests that PKC𝛼 and estrogen signal transduction pathways functionally interact to modulate ER-dependent growth and transcription.
Estrogen, acting through ER, is a major contributor to endometrial proliferation. Indeed, hormone-dependent, type I endometrial cancers are thought to arise due to excess estrogen stimulation, unopposed by progesterone, promoting mitogenesis, atypical hyperplasia, and the transition to malignant adenocarcinoma. In this study, the authors showed that activation of PKC𝛼 is a critical element of such an estrogenic environment, resulting in estrogen-independent activation of ER-dependent transcription and potentiating the effects of estrogen on both gene expression and endometrial cancer cell proliferation. The primary effect of PKC𝛼 is to stimulate basal, unliganded ER transactivation, thereby amplifying estrogen-stimulated promoter activity and enhancing levels of genes linked to endometrial hyperplasia and malignancy.
In summary, study showed that activation of PKC𝛼 induces estrogen-independent activation of ER-dependent gene expression and potentiates the effects of estrogen on transcription. Evidence also implicates PKC𝛼 in the regulation of estrogen-dependent endometrial cancer cell proliferation. Thus, PKC𝛼-dependent signal transduction is a critical component of the environment of excessive estrogen and supraphysiologic activation of ER, which is thought to underlie the development of endometrial hyperplasia and endometrioid adenocarcinoma. Furthermore, estrogen exposure may increase PKC𝛼 expression and/or activity in endometrial cancer cells providing a potential positive feedback loop to amplify estrogen and ER-dependent responses.
The incidence of endometrial cancer continues to rise, and despite advances in hormonal and chemotherapy, overall survival has not significantly improved. Thus, there is an evident need to develop novel, molecular targeted therapies. PKC𝛼 is a critical element in the estrogen, PI3K/Akt, and growth factor/ERK-dependent signal transduction pathways regulating the growth of type I tumors. Hence, inhibition of PKC𝛼-dependent signaling would enable the simultaneous targeting of multiple estrogen-dependent and independent pathways implicated in the development and progression of endometrial carcinogenesis. PKC𝛼-specific inhibitors [57–59] may provide novel avenues, for primary or adjunct therapeutic intervention, to target tumors resistant to current regimens.
Source: Hindawi Publishing Corporation. Obstetrics and Gynecology International, Volume 2013, Article ID 537479, 8 pages. http://dx.doi.org/10.1155/2013/537479
