Progesterone action in breast, uterine, and ovarian cancers

Abstract

Progesterone and progesterone receptors (PRs) are essential for the development and cyclical regulation of hormone-responsive tissues including the breast and reproductive tract. Altered functions of PR isoforms contribute to the pathogenesis of tumors that arise in these tissues. In the breast, progesterone acts in concert with estrogen to promote proliferative and pro-survival gene programs. In sharp contrast, progesterone inhibits estrogen-driven growth in the uterus and protects the ovary from neoplastic transformation. Progesterone-dependent actions and associated biology in diverse tissues and tumors are mediated by two PR isoforms, PR-A and PR-B. These isoforms are subject to altered transcriptional activity or expression levels, differential crosstalk with growth factor signaling pathways, and distinct post-translational modifications and cofactor-binding partners. Herein, we summarize and discuss the recent literature focused on progesterone and PR isoform-specific actions in breast, uterine, and ovarian cancers. Understanding the complexity of context-dependent PR actions in these tissues is critical to developing new models that will allow us to advance our knowledge base with the goal of revealing novel and efficacious therapeutic regimens for these hormone-responsive diseases.

Keywords: breast cancer; endometrial cancer; isoforms; ovarian cancer; progesterone; progesterone receptor; progestin; uterine.

Figure 1. The post-translational modifications of progesterone receptors

17 post-translational modification sites that impact PR-mediated transcriptional action. PR-B, but not PR-A, includes 164 additional amino acids in the NTD (called B upstream segment) where the third activation function domain and multiple phosphorylation sites are located. PR-B and PR-A are transcribed from the same gene and their protein isoforms are identical from amino acids 165-993. The protein tertiary structure results in a folding at the hinge region between the DBD and HBD. Post-translational modifications (phosphorylation, acetylation, and SUMOylation) can occur basally or in response to ligand binding and affect PR transcriptional activity. In particular, activated protein kinase pathways input to PR via phosphorylation and these pathways are heavily altered in breast, ovarian, and uterine carcinomas. Numbering reflects amino acid residue positions. The color of phosphorylation sites is associated with the following: red = MAPK; green = CDK2; yellow = CK2; purple = unknown kinases. PR, progesterone receptor protein isoforms A, B, or C; NTD, N-(amino)-terminal domain; DBD, DNA binding domain; H, hinge region; HBD, hormone binding domain; AF, activation function 1-3; P, phosphorylation; A, acetylation; SUMO, small ubiquitin-like modifier (SUMOylation). Dysregulation of Kinase Inputs to PR in Cancer: The percent of TCGA (The Cancer Genome Atlas) tumors containing alterations in MAPK, CDK2, or CK2 components were identified using the cBioPortal.org analysis tool. For analysis of dysregulated kinases: MAPK includes canonical c-Raf, Mek, and Erk signaling pathway genes: RAF1, MAP3K1, MAP3K2, MAPK3, MAPK1; CKD2, cyclin-dependent kinase 2; CK2, casein kinase 2, alpha 1 polypeptide, CSNK2A1.

Figure 2. Progesterone receptor action in the normal mammary gland

Pictured here in cross-section, alveoli are the primary glandular structures of the breast that form in groups (lobules) that are connected to the nipple through a network of ducts embedded within supporting stromal and adipose cells. Each alveolar unit contains a hollow lumen surrounded by a layer of apical luminal epithelium and basal myoepithelium (that are contractile and help with milk secretion during pregnancy). A basement membrane separates the epithelium from the surrounding adipose and stroma (that includes infiltrating immune cells, connective tissue, fibroblasts, and endothelium). The epithelium is derived and maintained from a population of self-renewing mammary stem cells. As illustrated in the inset, the majority of these mammary epithelial cells undergoing cell cycle progression (expressing cyclin D1) receive their proliferative signals via paracrine growth factor production (AREG, IGFs, and HBEGF) from nearby PR-positive cells. PR-positive cells also produce paracrine factors to maintain the mammary stem cell compartment, including WNT4 and RANKL. During early events in breast tumorigenesis, non-dividing PR+ cells (that express cell cycle inhibitors p21 and p27) may overcome cell cycle inhibition and actively begin proliferation via autocrine signaling. PR, progesterone receptor; AREG, amphiregulin; RANKL, receptor activator of nuclear factor kappa-B ligand; WNT4, wingless-type MMTV integration site family, member 4; IGF, insulin-like growth factor; HBEGF, heparin-binding EGF (epidermal growth factor)-like growth factor; D1, cyclin D1, CCND1; p21, cyclin-dependent kinase inhibitor 1A, CDKN1A; p27, cyclin-dependent kinase inhibitor 1B, CDKN1B; MaSC, mammary stem cell

Figure 3. Epithelial-stromal interactions regulating proliferation and differentiation of the uterine endometrium

The uterine endometrium is stylized in this figure, with predominant signaling pathways represented during the proliferative follicular phase of the menstrual cycle (above dotted line) and during the differentiation of the luteal phase (below dotted line). Arrows on the right indicate relative concentrations of circulating steroid hormone levels. During the follicular phase, the predominant steroid, estrogen (E2; estradiol), acts through its receptor (ER; expressed in epithelium and stroma) to activate the PI3K/Akt pathway and promote inhibitory phosphorylation of GSK-3β, leading to activation of Wnt signaling, regulation of cell cycle proteins and enhanced cell proliferation. E2 also can induce the expression of critical growth factors such as Wnt ligands, IGF1, and FGFs that are secreted by the epithelia and stroma, and which bind to epithelial membrane receptors (i.e. receptor tyrosine kinases, RTKs) to support proliferation. During the luteal phase and early pregnancy, progesterone (P4), as the predominant hormone, antagonizes E2-induced proliferation and promotes differentiation of the glandular epithelium. P4 acts through its receptor (PR) to induce expression of indian hedgehog (IHH) within the epithelium, which binds to Patched (PTCH) on the surface of the stromal cells and through the COUP-TFII and Hand2 complex inhibits expression of FGFs. In addition, P4 also appears to induce the stromal expression of the Wnt signaling antagonist, dickkopf-related protein 1 (DKK1) and the transcription factor, FOXO1, which leads to inhibition of Wnt signaling, inhibition of cell cycle progression, and expression of decidualization-specific genes for stromal cell differentiation. Frequent alterations in endometrial cancer include altered ER/PR expression, PTEN loss of function, activation of PI3K/AKT signaling, and mutations to FGFR; these events are predicted to impact PR actions in the context of tumorigenesis.

Figure 4. Cellular origins of ovarian cancer

Ovarian cancer is a collective term for several distinct invasive diseases that originate in the peritoneal cavity. Inset, the known sites of origin associated with the major histopathological subtypes of ovarian cancer. Mucinous ovarian cancers are metastases on the ovary from the gastrointestinal tract, including the stomach, colon, or appendix. Endometrioid and clear cell ovarian cancers are derived either from the cervix or from the uterus via progression of endometriosis, which is linked to retrograde menstruation from the endometrium. High-grade serous ovarian cancers are either derived from metastases from the distal fallopian tube or from the surface of the ovary.