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

Jorge Diaz, Evelyn Aranda, Soledad Henriquez, Marisol Quezada, Estefanía Espinoza, Maria Loreto Bravo, Bárbara Oliva, Soledad Lange, Manuel Villalon, Marius Jones, Jan J. Brosens, Sumie Kato, Mauricio A. Cuello, Todd P. Knutson, Carol A. Lange, Lisette Leyton, Gareth I. Owen

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mech- anisms 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.

Original languageEnglish (US)
Pages (from-to)165-175
Number of pages11
JournalJournal of Endocrinology
Volume214
Issue number2
DOIs
StatePublished - Aug 2012
Externally publishedYes

Fingerprint

PAR-1 Receptor
Focal Adhesions
Progesterone
Progesterone Receptors
Breast Neoplasms
Progestins
Cell Movement
Proteinase-Activated Receptors
Focal Adhesion Protein-Tyrosine Kinases
Stress Fibers
Messenger RNA
Peptides
Data Mining
Serine Proteases
Blood Coagulation
Proline
Serine
Signal Transduction
Therapeutics
Phosphorylation

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1. / Diaz, Jorge; Aranda, Evelyn; Henriquez, Soledad; Quezada, Marisol; Espinoza, Estefanía; Bravo, Maria Loreto; Oliva, Bárbara; Lange, Soledad; Villalon, Manuel; Jones, Marius; Brosens, Jan J.; Kato, Sumie; Cuello, Mauricio A.; Knutson, Todd P.; Lange, Carol A.; Leyton, Lisette; Owen, Gareth I.

In: Journal of Endocrinology, Vol. 214, No. 2, 08.2012, p. 165-175.

Research output: Contribution to journalArticle

Diaz, J, Aranda, E, Henriquez, S, Quezada, M, Espinoza, E, Bravo, ML, Oliva, B, Lange, S, Villalon, M, Jones, M, Brosens, JJ, Kato, S, Cuello, MA, Knutson, TP, Lange, CA, Leyton, L & Owen, GI 2012, 'Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1', Journal of Endocrinology, vol. 214, no. 2, pp. 165-175. https://doi.org/10.1530/JOE-11-0310
Diaz, Jorge ; Aranda, Evelyn ; Henriquez, Soledad ; Quezada, Marisol ; Espinoza, Estefanía ; Bravo, Maria Loreto ; Oliva, Bárbara ; Lange, Soledad ; Villalon, Manuel ; Jones, Marius ; Brosens, Jan J. ; Kato, Sumie ; Cuello, Mauricio A. ; Knutson, Todd P. ; Lange, Carol A. ; Leyton, Lisette ; Owen, Gareth I. / Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1. In: Journal of Endocrinology. 2012 ; Vol. 214, No. 2. pp. 165-175.
@article{62e84b1304dd42d48e0aabbfa1adda71,
title = "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 mech- anisms 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.",
author = "Jorge Diaz and Evelyn Aranda and Soledad Henriquez and Marisol Quezada and Estefan{\'i}a Espinoza and Bravo, {Maria Loreto} and B{\'a}rbara Oliva and Soledad Lange and Manuel Villalon and Marius Jones and Brosens, {Jan J.} and Sumie Kato and Cuello, {Mauricio A.} and Knutson, {Todd P.} and Lange, {Carol A.} and Lisette Leyton and Owen, {Gareth I.}",
year = "2012",
month = "8",
doi = "10.1530/JOE-11-0310",
language = "English (US)",
volume = "214",
pages = "165--175",
journal = "Journal of Endocrinology",
issn = "0022-0795",
publisher = "Society for Endocrinology",
number = "2",

}

TY - JOUR

T1 - Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1

AU - Diaz, Jorge

AU - Aranda, Evelyn

AU - Henriquez, Soledad

AU - Quezada, Marisol

AU - Espinoza, Estefanía

AU - Bravo, Maria Loreto

AU - Oliva, Bárbara

AU - Lange, Soledad

AU - Villalon, Manuel

AU - Jones, Marius

AU - Brosens, Jan J.

AU - Kato, Sumie

AU - Cuello, Mauricio A.

AU - Knutson, Todd P.

AU - Lange, Carol A.

AU - Leyton, Lisette

AU - Owen, Gareth I.

PY - 2012/8

Y1 - 2012/8

N2 - Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mech- anisms 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.

AB - Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mech- anisms 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.

UR - http://www.scopus.com/inward/record.url?scp=84866289319&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866289319&partnerID=8YFLogxK

U2 - 10.1530/JOE-11-0310

DO - 10.1530/JOE-11-0310

M3 - Article

VL - 214

SP - 165

EP - 175

JO - Journal of Endocrinology

JF - Journal of Endocrinology

SN - 0022-0795

IS - 2

ER -