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The rise and fall in ovarian oestrogen and progesterone production orchestrates a series of events that are indispensable for reproduction, including ovulation, implantation, decidualisation and menstruation. In the uterus, these events involve extensive tissue remodelling, characterised by waves of endometrial cell proliferation, differentiation, recruitment of inflammatory cells, apoptosis, tissue breakdown, menstruation and regeneration. The ability of ovarian hormones to trigger such diverse physiological responses is foremost dependent upon interaction of activated steroid receptors with specific transcription factors, such as Forkhead box class O (FOXO) proteins, involved in cell fate decisions. Furthermore, micro-RNAs (miRNAs), small non-coding RNAs that function as posttranscriptional regulators of gene expression, have emerged as a major regulator system of steroid hormone responses in the female reproductive tract. Consequently, increasing evidence shows that deregulated uterine miRNA expression underpins a spectrum of common reproductive disorders, ranging from implantation failure to endometriosis. Furthermore, by targeting FOXO transcription factors and other key regulators of tissue homeostasis, oncogenic endometrial miRNAs promote tumourigenesis and cancer progression.
Departamento de Fisiología, Departamento de Ginecología, Clinical Sciences Research Laboratories, Departments of Medicine and Pharmacology, Centro de Estudios Moleculares de la Célula (CEMC), Biomedical Research Consortium (BMRC) Chile, Facultad de Ciencias Biológicas and
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Departamento de Fisiología, Departamento de Ginecología, Clinical Sciences Research Laboratories, Departments of Medicine and Pharmacology, Centro de Estudios Moleculares de la Célula (CEMC), Biomedical Research Consortium (BMRC) Chile, Facultad de Ciencias Biológicas and
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Departamento de Fisiología, Departamento de Ginecología, Clinical Sciences Research Laboratories, Departments of Medicine and Pharmacology, Centro de Estudios Moleculares de la Célula (CEMC), Biomedical Research Consortium (BMRC) Chile, Facultad de Ciencias Biológicas and
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Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mechanisms are still not fully understood. The protease-activated receptors (PARs) are a family of membrane receptors that are activated by serine proteases in the blood coagulation cascade. PAR1 (F2R) has been reported to be involved in cancer cell migration and overexpressed in breast cancer. We herein demonstrate that PAR1 mRNA and protein are upregulated by progesterone treatment of the breast cancer cell lines ZR-75 and T47D. This regulation is dependent on the progesterone receptor (PR) but does not require PR phosphorylation at serine 294 or the PR proline-rich region mPRO. The increase in PAR1 mRNA was transient, being present at 3 h and returning to basal levels at 18 h. The addition of a PAR1-activating peptide (aPAR1) to cells treated with progesterone resulted in an increase in focal adhesion (FA) formation as measured by the cellular levels of phosphorylated FA kinase. The combined but not individual treatment of progesterone and aPAR1 also markedly increased stress fiber formation and the migratory capacity of breast cancer cells. In agreement with in vitro findings, data mining from the Oncomine platform revealed that PAR1 expression was significantly upregulated in PR-positive breast tumors. Our observation that PAR1 expression and signal transduction are modulated by progesterone provides new insight into how the progestin component in hormone therapies increases the risk of breast cancer in postmenopausal women.
