The functional PGR gene has 8 exons and 7 introns. The 13,748 bps transcript is translated into 933 residues The gene has 11 splice variants. It uses separate promoters and translational start sites in Exon 1 to produce two principal isoforms, PR-A and PR-B (http://grch37.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000082175;r=11:100900355-101001255).

The isoforms PR-A and PR-B are the products of a single gene. The top Figure 3 shows the use of separate promoters and translational start sites to produce the two principle PR isoforms PR-A (94 kDa) and PR-B (118 kDa). The isoforms contain a DNA binding domain and a ligand binding domain. N-terminal to the DBD is an AF-1 (activation function -1) and in the C-terminal direction a nuclear localisation signal and the LBD containing AF-2. The PR-B isoform has a 164 aminoacid stretch at the N-terminus with an AF-3 (Figure 3c). It is believed that AF-1 is thought to mediate ligand-independent activity, whilst AF-2 is attributed wih ligand-dependent PR activation. The N-terminal inhibitory subdomain of ?155 amino acids is not shown; The inhibitory domain does not function in the PR-B isoform. AF-1 is about 456-546. The third isoform is the splice variant PR-C. PR-C can bind the ligand, but in the absence of the DBD would not be able to bind to PREs of target genes.
Alternatively spliced variants
Many truncated splice variants of PR are generated and these are not easily detected by standard anti-PR antibodies (Cork et al. 2012) and often specimens may be designated as PR-negative. However, in the absence of firm evidence that these are functionally relevant in the cancer process, the inability to detect them may not be of much consequence.
Besides the three major isoforms, several splice variants of the gene have been identified. These are a result of the deletion of some of the eight exons of PR or by the retention of intronic sequences (see Cork et al. 2008). Two variants were translated into protein and were found to be differentially expressed in the endometrium (Springwald et al. 2010). However, the functional status of the variants is unclear. Variants with the deletion of exons 4, 6 and 4/6 (delta exons), and another one with partly deleted exon 6 have been identified. Their expression was higher in early/mid proliferative endometrium than in the secretory phase (Marshburn et al. 2005). This suggests that they might be functionally not relevant. For, in the proliferative phase oestrogen induces high mitotic activity in the epithelium and the stroma. The secretory phase is characterised by the action of progesterone towards the differentiation of the endometrium.
It ought to be pointed out here that the PR delta 4/6 showed a slight difference in expression between 1/45 normal and 5/45 breast cancer tissues of the patients (Nagao et al. 2003). Whilst reports of deletion variants are many, some earlier work has claimed the detection of insertion variants. One such is a variant with a 232 bp nucleotide insertion sequence between exons 4 and 5 in normal endometrium (Yamanaka et al. 2002). However, in the absence of information whether the variant transcript is translated, the inference of a potential relevance in normal or pathological condition of the endometrium is not warranted.
Splice variants: PR-delta4, PR-delta6, PR-delta6/7, PR-T, PR-S, PR-M, PR-i45 (insertion variant) i45a and i45b.

PR is expressed ubiquitously in human tissues as homo- or heterodimers. The isoforms are expressed in relatively equal abundance in most target tissues. In the event of neoplastic transformation, the isoforms might be differentially expressed and display progressive changes (see Scarpin et al. 2009).

Function and Signalling
Progesterone signalling generates its physiological effects by the conventional canonical nuclear receptor (PR) pathway and also by the seven-pass membrane receptor (mPR). The nuclear receptor PR is a transcription regulator. Upon ligand binding the principal isoforms PR-A and PR-B homo- or hetero-dimerize and function as transcription factors. The binding of ligands, agonist or antagonist, initiates a conformational change in PR leading to its translocation to the nucleus and binding to PRE of the responsive genes. The possibility that PR might function via a non-genomic mode cannot be excluded.
The rapidity of some responses to progesterone has suggested the presence of extranuclear receptor, such as the membrane associated mPRs and PGRMC1 (progesterone receptor membrane component 1). The mPRs are GPCRs belonging to the PAQR (progestin and adipoQ receptor) gene family (Tang et al, 2005. The mPRs and the PGRMC proteins belonging to a different family are encoded by different genes. It has been noted that target cells may respond to progesterone and produce biological effects via the mPRs and the PGRMC1. This would involve the engagement and activation of allied signalling systems that culminate in the phenotypic outcome. The mPRs function like GPCRs and also directly interacts with progestrone. The physiological outcome can occur independently of PR. PGRMC1 can directly interact with progesterone even in the absence of PR. The present indications are that both increase cell proliferation and migration. In fact, PGRMC1 may also facilitate cell proliferation and tumour growth. A small molecule inhibitor of PGRMC1 counteracts these effects. This inhibitor also destabilises EGFR expression, which would suggest that the PGRMC1 effects are to mediated by interaction with EGFR (Ahmed et al. 2010a, b). Although cell proliferative signalling does seem to be modulated by mPRs and the PGRMC1, there is a need to resolve whether mPRs and PGRMC1 work in the same phenotypic direction or exert opposing effects. Recent developments make it imperative that the non-canonical mode of progesterone signalling is borne in mind while assessing the validity of PR in breast cancer management
The PR-mediated response to progesterone involves Wnt signalling, PI3K/Akt/ MAPK signalling; the phenotypic outcome is on cell adhesion, proliferation and apoptosis. The ER/PR signalling axis has assumed much significance in the management of breast cancer patients. However, interpretation of their expression and physiological effects are complicated by several factors. The cell proliferation/survival results depend upon the ER/PR signalling axis subject to the provision of which isoform of ER or PR is functional and the recognition that ER does influence PR function. ERα and ERβ are two ER isoforms. ERα is pro-proliferation whilst ERβ is inhibitory of cell proliferation. ERα binds to and downregulates PR. The PR-A promoter does contain an ERE half site/Sp1 binding site and ER does bind directly to this site (Petz and Nardulli. 2000). Three functionally different PR isoforms of PR, viz. PR-A, PR-B and PR-C have been identified (reviewed by Kariagina et al. 2008). High PR-A expression has correlated with tumour relapse and with associated mutations in the breast cancer susceptibility genes BRCA1 andBRCA2 (Hopp eet al. 2004; Mote et al.2004). The differential expression of the isoforms may be due to methylation (Pathiraja et al. 2011). The PR-A and PR-B isoforms seem to regulate different sets of target genes. PR-B isoform is associated with increase in cell migration but not on cell proliferation or survival. Suppression of PR-B inhibits cell migration. Many publications have reported contradictory phenotypic effects of PR agonists and antagonists. These are most likely the outcome of the differential signalling by the canonical and the non-canonical receptors, which is not often taken into cognisance. The differential signalling is highlighted in Figure 5
The ER/PR signalling axis displays a complex circuitry of interaction and inter-regulation. When ER is non-functional the hormonal response is attenuated. When functional, ER can induce the expression of PR. Equally, PR can regulate ER function. In breast cancer cells, both oestrogen and progesterone can activate the Src/Erk pathway. PR possesses two domains that can interact with the ligand-binding domain of ERα and in this way mediate the activation of Src signalling (Ballaré et al. 2003). In fact, PR may regulate ER function in breast cancer and possibly also negatively regulate other oestrogen-activated signalling to suppress cell proliferation (Mohammed et al. 2015). Besides operating the canonical path of genetic transcription by binding to EREs in responsive genes, the ER can also function in a non-genomic fashion which does not involve direct genetic regulation. ER can influence cell proliferation by the activation of PI3K/MAPK signalling. Also, the G-protein coupled receptor GPCR30 has been recognised as a membrane receptor of oestrogen and the activation of GPCR30 leads to signalling by the non-genomic mode. The oestrogens produce many physiological effects by activating of GPCRs and driving PI3K/Akt and MAPK/ERK signalling. Oestrogens can also upregulate the expression of MMPs and promote invasion. Therefore, the overall outcome would be a result of the balance of activation of the ESR1/PR axis, including the balance of the PR isoforms. This probably applies also to the promotion or inhibition of inflammatory responses. Presumably, this is one of the reasons why so much controversy has surrounded the clinical value of PR in breast cancer, which is nonetheless shown to be a significant factor in patient management (reviewed by Sherbet, 2011, 2017). Another caveat to be considered is that the ER/PR signalling axis may be influenced by neighbouring genes such as the YAP1/ TAZ of the Hippo system.

PGR mutations are infrequent in cancers; the frequency is around 1% for all cancers. Mis-sense mutations were the most frequent type. The mutation frequency for endometrial cancer, adenocarcinoma of the stomach, cutaneous melanoma, small cell lung cancer (SCLC), and oesophageal carcinoma was between 2.6% to 4.4% of samples with PAMs (point accepted mutations). The frequency of all PGR mutation for breast cancer was 0.52% and for ovarian cancer 0.32 (IntOGen; www.intogen.org/search?gene=PGR).
Among the many polymorphic forms of the PGR gene is the polymorphism called PROGINS. This has a PV/HS-1 Alu insertion in intron 7 and two point mutations, V660L in exon 4 and H770H in exon 5. The Alu element has a half ERE/Spl binding site, which enhances the transcription function of PROGINS in response to oestradiol (Agoulnik et al. 2004). PROGINS may be associated with enhanced risk of ovarian, breast and prostate cancer (Leite et al. 2008; Govindan et al. 2007; Engehausen 2005). Equally, some studies have denied the link of PROGINS with cancer risk.
Over the past decade several SNPs in the PGR gene have been identified; many are inconsequential ones, but some have been related to possible links to the risk of development of breast, endometrial and colorectal cancers and endometriosis. The SNPs occur in the exons and some in the promoter region of the gene which is thought to have altered the expression of the receptor. These findings have not enabled substantive conclusions regarding their significance to the disease process. The presence of SNPs in the ER genes should also be sought whilst looking any PGR abnormalities. The perceived changes in the expression of PGR transcripts or the proteins cannot be assumed to be a direct consequence of the SNPs in PGR genes. The latter could well be a secondary outcome of alterations in ER.