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Distinct molecular pathways mediate progesterone-induced growth inhibition and focal adhesion
Valerie C L Lin1, Chow Thai Woon, Swee Eng Aw
1Department of Clinical Research, Singapore General Hospital, School of Biological Sciences, School, Singapore 637616. cllin@ntu.edu.sg.
Abstract:
We have reported previously that reactivation of progesterone receptor (PR) expression in estrogen receptor (ER)- and PR-negative MDA-MB-231 breast cancer cells enabled progesterone to inhibit cell growth and invasiveness, and to induce remarkable focal adhesions. The present study addressed molecular mechanisms that mediate these anticancer effects of progesterone in the PR-transfected breast cancer cells ABC28. In response to progesterone treatment are the marked up-regulation of cyclin-dependent kinase inhibitor protein p21WAF1/CIP1 and decreased expression of cyclin A, cyclin B1, and cyclin D1 that are required for G1 progression and during cell mitosis. Progesterone also induced down-regulation of phosphorylated MAPK (p42/44 MAPK). Furthermore, this study also demonstrated that MEK inhibitor PD98059 that inhibits the phosphorylation of p42/44 MAPK also caused reduction of cyclin D1 level and inhibition of cell proliferation. These results suggest that inhibition of p42/44 MAPK pathway is part of the mechanisms mediating progesterone's growth-inhibitory effect. On the other hand, progesterone-induced focal adhesion is mediated by separate pathway. Whereas PD98059 exhibited no effects on cell adhesion, inhibitory antibody to beta1-integrin was able to reverse progesterone-induced focal adhesion and progesterone-induced increase in the phosphorylation of focal adhesion kinase. On the other hand, beta1-integrin antibody had no effect on progesterone-mediated growth inhibition and on progesterone-mediated expression of cyclins p21CIP1/WAF1 and phosphorylation of P42/P44 MAPK. In the context of complex functions of progesterone in breast cancer and reproductive organs, identification of distinct pathways offers new strategies for designing therapeutic agents to target the specific pathway so as to minimize the side effects.
Insights
Progesterone inhibits breast cancer growth by down-regulating MAPK signaling and affecting cell cycle proteins. It also promotes focal adhesions via a separate beta1-integrin pathway, offering targeted therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Estrogen receptor (ER)- and progesterone receptor (PR)-negative breast cancer cells can regain sensitivity to progesterone's effects upon PR expression.
- Progesterone has demonstrated potential in inhibiting cancer cell growth and invasiveness while promoting focal adhesions.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the anticancer effects of progesterone in PR-transfected breast cancer cells (ABC28).
- To differentiate the pathways mediating progesterone's effects on cell proliferation and focal adhesion.
Main Methods:
- Treatment of ABC28 cells with progesterone and analysis of protein expression (p21WAF1/CIP1, cyclins A, B1, D1, phosphorylated MAPK).
- Utilized MEK inhibitor PD98059 to assess the role of MAPK pathway.
- Employed beta1-integrin antibody to investigate the focal adhesion pathway.
Main Results:
- Progesterone upregulated p21WAF1/CIP1 and downregulated cyclins A, B1, D1, and phosphorylated MAPK (p42/44 MAPK).
- MEK inhibitor PD98059 mimicked progesterone's effect on cyclin D1 and proliferation, suggesting MAPK pathway involvement in growth inhibition.
- Progesterone-induced focal adhesion was mediated by beta1-integrin and focal adhesion kinase phosphorylation, independent of the MAPK pathway.
Conclusions:
- Progesterone inhibits breast cancer cell proliferation through the MAPK pathway.
- Distinct pathways mediate progesterone's effects on growth inhibition and focal adhesion.
- Identifying these separate pathways provides opportunities for developing targeted breast cancer therapies with minimized side effects.