Growth inhibition of human salivary gland tumor cells by introduction of progesterone (Pg) receptor and Pg treatment

Abstract

Cancer of the salivary gland is one of the common cancers in the head and the neck regions. This type of cancer develops in the minor and the major salivary glands, and it sometimes metastasizes to other organs, particularly the lung. Morphologic mimicry and similarity in the expression of steroid hormone receptors between salivary gland tumors (SGTs) and breast tumors are well-known phenomena and are occasionally debated in the field of surgical pathology. Progesterone (Pg), one of the female sex steroid hormone, is intimately involved in the development of the mammary gland. Further, it is believed that Pg plays a role in breast cancer progression. However, little is known regarding its role in SGTs. In this study, we used ACCM, a human adenoid cystic carcinoma cell line established from the salivary gland, in order to clarify the role of the Pg receptor (PR) on cell proliferation. No effect of Pg on cell proliferation was observed in the PR-deficient aggressive ACCM cells. However, after introducing PR into the ACCM cells, Pg markedly inhibited the proliferative activity of the cells. This inhibitory effect on cell proliferation was accompanied by p21 upregulation, and Id1 and c-myc downregulation. Moreover, Pg-treated PR transfectants showed significant morphological change; they appeared more flattened and spread out when compared with the ethanol-treated control cells. Our results provided significant insights into the mechanism of suppression of the proliferative property of the cells via the function of PR, and suggested that PR reintroduction therapy might be a viable method of inhibiting human SGT progression.

Suppression of invasion and metastasis in aggressive salivary cancer cells through targeted inhibition of ID1 gene expression

“…We previously reported that aggressiveness was reduced in PR-deficient human aggressive breast cancer cells after PR was reintroduced and treated with Pg [20]. Further, we found that Pg could act as an inhibitor of SGC cell proliferation [13]. In these two studies, we reported that progesterone-induced growth inhibition was accompanied by both up-regulation of p21, which generally plays a critical role in regulating cell growth inhibition [13].…”

“…Pooled cell populations of PR-expressing cells were prepared as previously described [13]. Briefly, a pSG5 plasmid was used to introduce vectors hPR1 and hPR2, which contained human PR cDNA coding for isoforms PR-B and PR-A, respectively.…”

“…We previously transfected progesterone receptor (PR) isoforms into the ACCM metastatic SGC cell line, then observed how progesterone (Pg) treatment impacted their migration and invasion through the down-regulation of ID1 gene expression [13]. Metastatic SGC cells transfected with PR exhibited lower levels of migration and invasion after Pg treatment than those treated only with an ethanol control.…”

Hormone Therapy for the Treatment of Patients with Malignant Salivary Gland Tumor (MSGT)

“…2). Specifically, we demonstrated that after transduction of PR, progesterone could significantly suppress the proliferation (and invasion) of MSGT cells (Yoshimura et al, 2007). This suppression did not lead to cell death, but instead to cell cycle arrest.…”

“…Although a number of studies have been published, the rationale for hormone therapy of MSGTs remains controversial because of disparate results and an insufficient number of cases. However, some recent studies have shown that certain salivary gland neoplasms are similar to breast cancer, not only in terms of their pathological features, but also at the molecular level (Pia-Foschini, 2003;Wick et al, 1998;Yoshimura et al, 2007). Here, we shed light on the biological similarity between MSGTs and certain types of breast cancer, and describe the potential use of hormone and additional therapies for MSGTs.…”