Lost but Not Least-Novel Insights into Progesterone Receptor Loss in Estrogen Receptor-Positive Breast Cancer

Abstract

Estrogen receptor α (ERα) and progesterone receptor (PgR) are crucial prognostic and predictive biomarkers that are usually co-expressed in breast cancer (BC). However, 12-24% of BCs present ERα(+)/PgR(-) phenotype at immunohistochemical evaluation. In fact, BC may either show primary PgR(-) status (in chemonaïve tumor sample), lose PgR expression during neoadjuvant treatment, or acquire PgR(-) phenotype in local relapse or metastasis. The loss of PgR expression in ERα(+) breast cancer may signify resistance to endocrine therapy and poorer outcomes. On the other hand, ERα(+)/PgR(-) BCs may have a better response to neoadjuvant chemotherapy than double-positive tumors. Loss of PgR expression may be a result of pre-transcriptional alterations (copy number loss, mutation, epigenetic modifications), decreased transcription of the PGR gene (e.g., by microRNAs), and post-translational modifications (e.g., phosphorylation, sumoylation). Various processes involved in the down-regulation of PgR have distinct consequences on the biology of cancer cells. Occasionally, negative PgR status detected by immunohistochemical analysis is paradoxically associated with enhanced transcriptional activity of PgR that might be inhibited by antiprogestin treatment. Identification of the mechanism of PgR loss in each patient seems challenging, yet it may provide important information on the biology of the tumor and predict its responsiveness to the therapy.

Keywords: breast cancer; estrogen receptor; microRNA; progesterone receptor; treatment.

Figure 1

Interactions between PgR, growth factor-dependent signaling and MISS Green arrows demonstrate stimulatory effects, red T-shaped lines depict inhibition. Overactive growth factors receptors stimulate MISS and directly activate various signaling pathways leading to activation of multiple kinases, i.e., ERK, AKT, RSK2, mTORC1, which phosphorylate PgR at Ser294. Phosphorylated PgR is undersumoylated, undergoes rapid ubiquitination and degradation in proteasomes reflected by PgR(−) status in immunohistochemistry. Phosphorylated PgR is also transcriptionally overactive, recruits CBP and MLL2, and enhances transcription of genes involved in cancer progression. Abbreviations: AHR—aryl hydrocarbon receptor; AKT—protein kinase B; AR—androgen receptor; BRCA1—Breast cancer type 1 susceptibility protein; CBP—CREB-binding protein; ERα—estrogen receptor α; ERBB2—Erb-B2 Receptor Tyrosine Kinase 2; ERK—extracellular-regulated kinase; FGFR2—fibroblast growth factor receptor 2; HER2—human epidermal growth factor receptor 2; IGFR—insulin-like growth factor receptor; IHC—immunohistochemistry; MEK—mitogen-activated protein kinase; MISS—membrane-initiated steroid signaling; MLL2—mixed linage leukemia gene 2; mTORC1—mammalian target of rapamycin complex 1; P—phosphate residues; (m)PgR—(membranous) progesterone receptor; PAX2—paired box 2; Raf—rapidly accelerated fibrosarcoma; PDK1—3-phosphoinositide-dependent protein kinase-1; PI3K—phosphoinositide 3-kinase; PTEN—phosphatase and tensin homolog; RAS—rat sarcoma virus; RSK2—ribosomal S6 kinase 2; RUNX2—RUNX Family Transcription Factor 2; SERDs—selective estrogen receptor degraders; SERMs—selective estrogen receptor modulators; Ub—ubiquitin. Created with BioRender.com—accessed date 22 September 2021.

Figure 2

Pre-translational mechanisms of PgR loss and down-regulation. Green arrows indicate stimulatory effects, red T-shaped lines depict inhibitory effects, dotted lines show potential effects. At pre-transcriptional stage, PgR loss is a consequence of methylation of PGR promoter, copy number loss (often), or mutations (very rarely). Splice variants of ERα and ERβ may either suppress or activate the transcription of PGR. Low levels of estradiol after menopause are frequently insufficient to induce expression of PgR. PGR mRNA is a direct target of multiple miRNAs, but some miRNAs may down-regulate PgR indirectly, e.g., via activation of mTORC1. For details, see text. Abbreviations: AGO2—protein argonaute-2; ERα—estrogen receptor α; HER2—human epidermal growth factor receptor 2; miRNAs—microRNAs; MISS—membrane-initiated steroid signaling; mTORC1—mammalian target of rapamycin complex 1; PGR—progesterone receptor gene; PgR—progesterone receptor. Created with BioRender.com—accessed date 22 September 2021.

Figure 3

Biology of ERα(+)/PgR(+) and ERα(+)/PgR(−) breast cancer. Green arrows indicate stimulatory effects, red T-shaped lines depict inhibitory effects. In tumor cells co-expressing ERα and nuclear PgR the latter may exert both non-genomic and genomic effects. It regulates the expression of genes in a similar way to ERα (genomic agonism) but guides ERα binding to chromatin to induce expression of genes associated with good outcomes (phenotypic antagonism). PgR interacts with translational machinery (mainly RNA polymerase III) reducing its availability for ERα-dependent translation. Loss of nuclear PgR results in a shift of ERα role from distant enhancer to proximal promoter activating subset of genes associated with cancer progression. Depletion of PgR increases ESR1 gene promoter methylation and down-regulates ESR1. Other steroid receptors, i.e., ER and AR may exert different effects on ERα-dependent genes expression in ERα(+)/PgR(+) and ERα(+)/PgR(−) breast cancers. For details, see text. Abbreviations: AR—androgen receptor; ESR1—estrogen receptor 1 gene; ER—estrogen receptor; HRE—hormone receptor element; (m)PgR—(membranous) progesterone receptor, RNA pol III—RNA polymerase III. Created with BioRender.com—accessed date 22 September 2021.