Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1

Abstract

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.

Megestrol Acetate Increases the Proliferation, Migration, and Adipogenic Differentiation of Adipose-Derived Stem Cells via Glucocorticoid Receptor

“…In previous studies, progesterone increased the proliferation of mammary gland and pancreatic cells [19,20]. In addition, progesterone stimulated the proliferation of steroid receptor-positive breast cancer and increased the migration of breast cancer cells [21,22]. Progesterone also enhanced the immunoregulatory activity of mesenchymal stem cells [23].…”

Dabigatran Potentiates Gemcitabine-Induced Growth Inhibition of Pancreatic Cancer in Mice

“…Moreover, these increased PAR-1 levels are associated with disease progression and reduced overall survival in breast and lung cancer patients (9,10).…”

Overcoming inherent resistance to histone deacetylase inhibitors in multiple myeloma cells by targeting pathways integral to the actin cytoskeleton

“…A description of these genes and their association with the regulation of actin cytoskeleton pathway components are provided in Supplementary file 4. 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 As a number of genes known to be associated with the actin cytoskeleton pathway were differentially regulated between the HDACi-sensitive and resistant HMCL, we postulated that the targeting of single genes among those identified would be unlikely to reverse resistance to HDACi, rather it is the global effect of these factors that mediates HDACi resistance. The genes that we identified that are differentially regulated are associated with pathways that are integral to the regulation of actin cytoskeleton rather than being components of the latter.…”