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The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival.
Int J Oncol. 2005 Jun; 26(6):1507-15.IJ

Abstract

Overexpression of the lipogenic enzyme fatty acid synthase (FAS) is a common molecular feature in subsets of sex-steroid-related tumors including breast carcinomas that is associated with poor prognosis. In this study, we explored whether breast-cancer associated FAS (oncogenic antigen-519) is regulated by the progestin component in oral contraceptives. In addition, we examined the role of FAS hyperactivity on progestin-regulated breast cancer cell proliferation, survival and metastatic properties. We found that in estrogen receptor (ER)- and progesterone receptor (PR)-positive MCF-7 human breast cancer cells, synthetic progestins used in oral contraceptives including norethynodrel (NOR) and norethindrone, induced a dose-dependent increase of FAS enzymatic activity, with a maximum response (> or = 4-fold) occurring at a concentration of 10(-8) M. FAS activity was only slightly stimulated after exposure to two other progestins, medroxy-progesterone acetate (MPA) and megestrol acetate (MGA), which are used in postmenopausal hormone replacement therapy and high-dose progestin treatment therapy. Western blot analyses showed that NOR-induced stimulation of FAS activity correlated closely with NOR-induced up-regulation of FAS protein expression. To determine the role of FAS accumulation following NOR exposure, we pharmacologically examined the requirement for FAS activity in NOR-stimulated breast cancer cell proliferation and survival. The novel small compound C75 (a slow-binding FAS inhibitor) blocked NOR-induced breast cancer cell proliferation in anchorage-dependent assays. More importantly, pharmacological inhibition of FAS activity completely abolished NOR-stimulated soft-agar colony formation of MCF-7 cells. To evaluate the involvement of PR and ER signalings in NOR-induced up-regulation of FAS expression and activity, NOR was used in combination with either the anti-progestin RU486 (mifepristone) or the pure antiestrogen ICI 182,780 (Faslodex). RU486 and ICI 182,780 similarly abolished NOR-induced FAS activation, supporting the notion that PR- and ER-mediated FAS up-regulation might play different roles in NOR-stimulated breast cancer cells. Interestingly, when we evaluated the involvement of PR and ER signalings on NOR-induced breast cancer cell proliferation, the anti-estrogen ICI 182,780, but not the anti-progestin RU486, was found to inhibit NOR-stimulated proliferation and survival of MCF-7 cells in anchorage-dependent and -independent assays. To further determine whether NOR produced their effects via the ER, we evaluated its effects on endogenous ER transcriptional activity by using transient transfection assays with an estrogen-response element reporter construct (ERE-Luciferase). In the absence of E2 stimulation, treatment with NOR dramatically increased the levels of ERE-dependent transcriptional activity. This estrogenic like-effect of NOR was blocked by the addition of ICI 182,780, whereas RU486 failed to inhibit NOR-induced ERE activity. In summary, this study provides direct evidence that: a) a number of synthetic progestins used in oral contraceptives significantly activates breast cancer-associated FAS (OA-519) activity and expression in hormone-dependent breast cancer cells; b) FAS activity is necessary for progestin-induced anchorage-independent growth and survival of human breast cancer cells, and c) activation of ER, but not PR signaling, is the stimulatory mechanism through which synthetic progestins enhance a FAS-dependent proliferative and pro-survival signaling. These findings should be helpful to explain the conflicting evidence linking oral contraceptives and breast cancer risk through the estrogenic activation of tumor-associated FAS (OA-519), a molecular marker associated with poor clinical outcome of breast cancer disease.

Authors+Show Affiliations

Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

15870863

Citation

Menendez, Javier A., et al. "The Estrogenic Activity of Synthetic Progestins Used in Oral Contraceptives Enhances Fatty Acid Synthase-dependent Breast Cancer Cell Proliferation and Survival." International Journal of Oncology, vol. 26, no. 6, 2005, pp. 1507-15.
Menendez JA, Oza BP, Colomer R, et al. The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival. Int J Oncol. 2005;26(6):1507-15.
Menendez, J. A., Oza, B. P., Colomer, R., & Lupu, R. (2005). The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival. International Journal of Oncology, 26(6), 1507-15.
Menendez JA, et al. The Estrogenic Activity of Synthetic Progestins Used in Oral Contraceptives Enhances Fatty Acid Synthase-dependent Breast Cancer Cell Proliferation and Survival. Int J Oncol. 2005;26(6):1507-15. PubMed PMID: 15870863.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival. AU - Menendez,Javier A, AU - Oza,Bharvi P, AU - Colomer,Ramon, AU - Lupu,Ruth, PY - 2005/5/5/pubmed PY - 2005/7/27/medline PY - 2005/5/5/entrez SP - 1507 EP - 15 JF - International journal of oncology JO - Int J Oncol VL - 26 IS - 6 N2 - Overexpression of the lipogenic enzyme fatty acid synthase (FAS) is a common molecular feature in subsets of sex-steroid-related tumors including breast carcinomas that is associated with poor prognosis. In this study, we explored whether breast-cancer associated FAS (oncogenic antigen-519) is regulated by the progestin component in oral contraceptives. In addition, we examined the role of FAS hyperactivity on progestin-regulated breast cancer cell proliferation, survival and metastatic properties. We found that in estrogen receptor (ER)- and progesterone receptor (PR)-positive MCF-7 human breast cancer cells, synthetic progestins used in oral contraceptives including norethynodrel (NOR) and norethindrone, induced a dose-dependent increase of FAS enzymatic activity, with a maximum response (> or = 4-fold) occurring at a concentration of 10(-8) M. FAS activity was only slightly stimulated after exposure to two other progestins, medroxy-progesterone acetate (MPA) and megestrol acetate (MGA), which are used in postmenopausal hormone replacement therapy and high-dose progestin treatment therapy. Western blot analyses showed that NOR-induced stimulation of FAS activity correlated closely with NOR-induced up-regulation of FAS protein expression. To determine the role of FAS accumulation following NOR exposure, we pharmacologically examined the requirement for FAS activity in NOR-stimulated breast cancer cell proliferation and survival. The novel small compound C75 (a slow-binding FAS inhibitor) blocked NOR-induced breast cancer cell proliferation in anchorage-dependent assays. More importantly, pharmacological inhibition of FAS activity completely abolished NOR-stimulated soft-agar colony formation of MCF-7 cells. To evaluate the involvement of PR and ER signalings in NOR-induced up-regulation of FAS expression and activity, NOR was used in combination with either the anti-progestin RU486 (mifepristone) or the pure antiestrogen ICI 182,780 (Faslodex). RU486 and ICI 182,780 similarly abolished NOR-induced FAS activation, supporting the notion that PR- and ER-mediated FAS up-regulation might play different roles in NOR-stimulated breast cancer cells. Interestingly, when we evaluated the involvement of PR and ER signalings on NOR-induced breast cancer cell proliferation, the anti-estrogen ICI 182,780, but not the anti-progestin RU486, was found to inhibit NOR-stimulated proliferation and survival of MCF-7 cells in anchorage-dependent and -independent assays. To further determine whether NOR produced their effects via the ER, we evaluated its effects on endogenous ER transcriptional activity by using transient transfection assays with an estrogen-response element reporter construct (ERE-Luciferase). In the absence of E2 stimulation, treatment with NOR dramatically increased the levels of ERE-dependent transcriptional activity. This estrogenic like-effect of NOR was blocked by the addition of ICI 182,780, whereas RU486 failed to inhibit NOR-induced ERE activity. In summary, this study provides direct evidence that: a) a number of synthetic progestins used in oral contraceptives significantly activates breast cancer-associated FAS (OA-519) activity and expression in hormone-dependent breast cancer cells; b) FAS activity is necessary for progestin-induced anchorage-independent growth and survival of human breast cancer cells, and c) activation of ER, but not PR signaling, is the stimulatory mechanism through which synthetic progestins enhance a FAS-dependent proliferative and pro-survival signaling. These findings should be helpful to explain the conflicting evidence linking oral contraceptives and breast cancer risk through the estrogenic activation of tumor-associated FAS (OA-519), a molecular marker associated with poor clinical outcome of breast cancer disease. SN - 1019-6439 UR - https://www.unboundmedicine.com/medline/citation/15870863/The_estrogenic_activity_of_synthetic_progestins_used_in_oral_contraceptives_enhances_fatty_acid_synthase_dependent_breast_cancer_cell_proliferation_and_survival_ L2 - http://www.spandidos-publications.com/ijo/26/6/1507 DB - PRIME DP - Unbound Medicine ER -