**1. Introduction**

A certain minimal level of progesterone must be maintained from ovulation until delivery to allow the birth of a full-term live baby [1]. Progesterone (P), acting in conjunction with the P receptor, causes the production of a large number of various molecules needed for the development of an appropriate secretory endometrium to allow attachment of the blastocyst to the endometrium and adequate invasion to the proper depth of the fetal placental unit [1].

Some of the molecules induced are also needed to suppress rejection of the fetal semi-allograft. One of these immunomodulatory proteins has been termed the progesterone induced blocking factor (PIBF) [2]. There is evidence that PIBF is one of the most important immunomodulatory factors produced during pregnancy to inhibit immune rejection of the fetal semi-allograft [3, 4].

Progesterone-induced blocking factor is an immunomodulatory protein that can suppress or block various aspects of the immune system, especially, but not

limited to, natural killer (NK) cells [5, 6]. The blocking effect on cellular immunity, especially NK cell cytolytic activity, may be related, at least in part, to a shift from thymic helper (TH)-1 to TH2 cytokine dominance [7]. One mechanism by which PIBF can suppress NK cell cytolytic activity is by inhibiting degranulation of perforin granules, one mechanism used by NK cells to kill other cells [8].

The "parent" form has a molecular mass of 90 kDa and is localized in the centrosome [9]. Various splice variants of this nuclear protein lead to smaller intracytoplasmic molecules that have immunosuppressive activity [9]. The actual full-length protein contains 757 amino acids, and the 48 kDa N terminal part is biologically active [10]. The PIBF gene has been identified on chromosome 13 in the vicinity of breast cancer 1 (BRCA1) or BRCA2 or p53 [11, 12].

Progesterone-induced blocking factor rises precipitously in the serum after exposure to P (even in males injected with progesterone) and the source seems to be circulating gamma/delta T cells [2]. However, it seems that the main source of PIBF that allows the early feta-placental to escape immune surveillance are actually cells of the fetal placental unit namely embryonic cells, mesenchymal cells, and trophoblast cells [1, 9].

In 2001, Check et al. hypothesized that it is likely that cancer cells might "borrow" some of the same mechanisms to escape immune surveillance as the fetal-placental unit [13]. Based on their previous research with the PIBF protein, they considered that, whereas treatment for infertility or recurrent miscarriage should be aimed at increasing the production of the PIBF protein, theoretical treatment for cancer could be therapy aimed at suppressing the PIBF protein [13].

Support for this concept was provided by Lachman et al., who showed that many different types of cancer cells express this PIBF protein [9]. Though one may think that highly proliferating cancer cells may be the ones that have the classic nuclear progesterone present, the study by Lachman et al., found many of the cancers associated with PIBF were not known to be positive for the nuclear P receptor [9].

Based on this hypothesis, it was considered that a P receptor antagonist/ modulator should cause suppression of PIBF production in rapidly growing cancer cells which could overcome the theoretical block of immune function of cellular immune cells in the tumor microenvironment.

Mifepristone was the first P receptor antagonist developed [14]. It was a derivative of the synthetic progestin norethindrone [14]. It was purposely developed to be an abortifacient to alter the endometrium and cause decidual necrosis and cause the trophoblast to separate from the decidua [14–16]. Mifepristone sensitizes the pregnant uterus and cervix to endogenous and exogenous prostaglandins increasing uterine contractility and helps to induce cervical softening [14–16].

Over the years other benefits of mifepristone, related to its anti-progesterone effect, have been developed, including treating uterine leiomyomata and endometriosis [17]. The anti-abortifacient drug comes in 200 mg tablets. Since mifepristone in higher dosages blocks the glucocorticoid receptor, it has been approved as a 300 mg tablet to treat Cushing's syndrome [18].

Thus, we set up a study to determine if we could detect PIBF in various leukemia cell lines, and, if so, determine if adding mifepristone to the medium could reduce PIBF secretion. To do so we collaborated with Dr. Srivastava from the Roswell Park Cancer Institute, who for many years studied protein production by leukemia cell lines. Twenty-nine cell lines of diverse lineage were all found to express messenger (m) RNA for PIBF [19]. In fact, there was more mRNA dedicated to the production of the PIBF protein, by far, than any mRNA for any other protein previously studied in these leukemia cell lines [19]. Ten cell lines positive for mRNA for PIBF were tested for the PIBF protein using a much less sensitive assay for PIBF than is presently available. Four tested positive for the PIBF protein. Addition of progesterone to the

#### *Progesterone and Glucocorticoid Receptor Modulator Mifepristone (RU-486) as Treatment… DOI: http://dx.doi.org/10.5772/intechopen.93545*

media of the cell lines up-regulated mRNA for PIBF and also the PIBF protein [19]. In contrast, the addition of mifepristone to the media down-regulated both mRNA for PIBF and the 35 kDa PIBF intracytoplasmic splice variant protein (similar in size to the PIBF splice variant in fetal-placental cells) [19].

Subsequently studies using other cancer cell lines supported the conclusions from the leukemia cell line studies. Kyurkchiev et al. found that glioblastoma multiforme also express the intracytoplasmic PIBF protein, but in this case the splice variant measured 57 kDa [20]. Gonzalez-Arenas et al. found, similar to the aforementioned leukemia cell line studies, adding P to the media up-regulates the 57 kDa intracytoplasmic splice variant of PIBF in glioblastoma multiforme cell lines [21]. Interestingly, in addition they added PIBF protein to the media and found that PIBF increased the number of U87 cancer cells on days 4 and 5 of treatment. This suggests that PIBF promotes proliferation of human glioblastoma cancer cells independent of an intact immune system, which would require a whole intact animal or human [21].

Mifepristone has been also found to inhibit the growth of cell lines or murine tumor transplantation from endometrial cancer, breast cancer, prostate cancer, gastric cancer, ovarian cancer, and lung cancer [22–27].

Goyeneche's group published some interesting findings concerning mifepristone and ovarian cancer cell lines. They have found that mifepristone inhibits ovarian cancer cell growth in vitro and in vivo [28]. They have published several studies showing the benefit of the combination of mifepristone and chemotherapy with cisplatin therapy or cisplatin-paclitaxel treatment of ovarian cell lines [29–31].

Based on these cell line studies, more support was provided that cancer cells may borrow some of the same escape mechanisms as the fetal-maternal unit to escape immune surveillance. Thus, therapy aimed to suppress these immune factors could lead to novel effective anticancer therapies [32]. Dr. Szekeres-Bartho, another pioneer in determining that the immunomodulatory protein, PIBF, plays a major role in allowing the fetus to avoid immune surveillance, in 2010 wrote a treatise entitled "PIBF: the double-edged sword. Pregnancy and tumor" [33].

In an opinion entitled "Pregnancy is a model for tumors, not transplantation," the renowned immunologist Kenneth Beaman, and his group, in 2016, stated "Nearly 65 years have passed since Peter Medawar posed the following question: "How does the pregnant mother contrive to nourish within itself for many weeks or months, a fetus that is an antigenic foreign body." Now, understanding of reproductive immunology has demonstrated that the HLA antigens in the placenta are non-classical and do not induce rejection. In the placenta and in tumors, 50% or more of the cells are cells of the immune system and were once thought to be primed and ready for killing tumors or "the fetal transplant" but these cells are not potential killers but abet the growth of either the tumor or the placenta. By examining the similarities of the placenta's and tumor's immune cells, novel mechanisms to cause tumors to be eliminated can be designed. Thus, 15 years later, the concept we published in 2001 is starting to be accepted by top immunologists in the field [34]. Though Beaman et al. do not refer at all to the PIBF protein, I recommend an article in gynecologic oncology to those readers wanting further knowledge into the immune similarities between pregnancy and cancer to open the door for other novel treatments of malignant tumors other than blocking the progesterone receptor [35].
