Interplay between the levels of estrogen and estrogen receptor controls the level of the granzyme inhibitor, proteinase inhibitor 9 and susceptibility to immune surveillance by natural killer cells

Abstract

Estrogens promote cell proliferation and metastases in several human cancers. Here, we describe a different action of estrogens likely to contribute to tumor development-blocking immunosurveillance. In breast cancer cells, increasing concentrations of estrogen induce increasing levels of the granzyme B inhibitor, SerpinB9/proteinase inhibitor 9 (PI-9) and progressively block cell death induced by NK92 natural killer (NK) cells, but do not block killing by a second NK cell line, NKL cells. RNA interference knockdown of PI-9 abolishes estrogen's ability to block NK92 cell-induced cytotoxicity. Expressing elevated levels of estrogen receptor a (ERa) increases the induced level of PI-9, and makes tamoxifen (TAM), but not raloxifene or ICI 182,780, a potent inducer of PI-9. At elevated levels of ERa, induction of PI-9 by estradiol or TAM blocks killing by both NK92 and NKL cells. When the Erk pathway is activated with epidermal growth factor, the concentration of estrogen required to induce a protective level of PI-9 is reduced to 10 pM. Elevated concentrations of estrogen and ER may provide a dual selective advantage to breast cancer cells by controlling PI-9 levels and thereby blocking immunosurveillance. Expressing elevated levels of ERa reveals a potentially important difference in the effects of TAM, raloxifene and ICI 182,780 on immunosurveillance in breast cancer.

Prosaposin, a regulator of estrogen receptor alpha, promotes breast cancer growth

“…(10)(11)(12) Prosaposin (PSAP) exists as a secretory protein (70 kDa) as well as a lysosomal protein (65 kDa). The molecular weight difference depends on the post-translational glycosylation.…”

“…(6)(7)(8)(9) Estrogen receptor alpha promotes cell growth, metastasis and also mediates resistance to apoptosis or immunosurveillance in breast cancer. (10)(11)(12) Prosaposin (PSAP) exists as a secretory protein (70 kDa) as well as a lysosomal protein (65 kDa). The molecular weight difference depends on the post-translational glycosylation.…”

The analysis of estrogen receptor-α positive breast cancer stem-like cells unveils a high expression of the serpin proteinase inhibitor PI-9: Possible regulatory mechanisms

“…The proteinase inhibitor 9 (PI-9), a member of family of serine proteinase inhibitors, is a direct inhibitor of granzyme B in human (39). Its overexpression has been observed in several types of cancer, such as breast (28), prostate (40) and lung cancer (41) and has been correlated to the protection of tumor cells from granzyme B-mediated cytotoxicity. However, no data concerning the status of PI-9 in cancer stem cells are available so far.…”

“…In light of the results obtained on ERα receptor isoforms, our attention was next focused on PI-9 (proteinase inhibitor 9), a member of serpin family which is subjected to the hormonal induction mediated by ERα66-dependent transcriptional regulation (28). Since S3 tumorspheres showed a higher expression of ERα36 receptor which lacks transcriptional activity, we expected to find a lower level of PI-9 in tumorspheres than parental MCF7 cells.…”

A Competitive Inhibitor That Reduces Recruitment of Androgen Receptor to Androgen-responsive Genes

“…However, 10 M CPIC and 10 M bicalutamide alone had similar minimal effects on the proliferation of LNCaP cells. Tamoxifen, which competes with estrogens for binding to ER, exhibits partial agonist activity in stimulating gene expression in MCF-7 human breast cancer cells (50,51) but is widely used in breast cancer therapy. Because the weak agonist activity of CPIC in LNCaP cells does not stimulate of LNCaP cell proliferation, CPIC has therapeutic potential.…”