Improving the efficacy of hormonal therapy in MCF-7 breast cancer cells grown in the presence of IGF-I by targeting the MAPK/MEK and JAK/STAT cell survival signaling pathways

Abstract

Breast cancer is the leading cause of cancer and the second leading cause of cancer deaths in women in the United States. Approximately 30% of estrogen receptor positive breast cancers are inherently resistant to anti-estrogen therapy and the recurrence of breast cancer in women initially responsive ~o anti-estrogen treatment frequently occurs. Thus, new approaches to increase the efficacy of hormonal. therapy are needed. · Because epidemiological studies associate high IGF-I levels with a poor prognosis .for breast cancer patients, we inves.tigated the underlying mechanism(s) of IGF~l-mediated · protection. 4-Hydroxytamoxifen-and mifepristone-induced cell death is significantly attenuated by IGF-I. IGF-I induction of cell survival pathways was analyzed focusing on signaling pathways and it has been demonstrated that IGF-I-mediated protection ofMCF- 7 cells resulted_from activation of the MAPK/MEK and JAK/STAT signaling pathways. · Cell lifting and P ARP cleavage was · detected in tamoxifen-and m~fepristone-treated MCF-7 cells growing in the presence of IGF-I and PD98059, a MEK inhibitor and also in the presence of IGF-I and AG490, a JAK2 inhibitor. The amount of cleaved P ARP i:°MCF- 7 cells transfected with MEKl siRNA is higher in cells treated with estradiq\ 3/-~ne than with hormonal therapy. The MEKlsiRNA may cause growth arrest, interfering with the actions of the hormonal therapy. The degree of death caused by hormonal therapy in the absence and presence of IGF-I is similar indicating that MEKl has a role in the protection of MCF-7 cells from hormonal therapy-induced cell death Transfection of MCF-7 cells with dominant-negative JAK2 resulted in increased cell death. The JAK/STAT pathway appears to ·be an important pathway for the survival of breast cancer cells because even in the absence of hormonal therapy, as was evident by the death of the MCF-7 cells with the dominant-negative JAK2 constructs. Higher levels ?f PARP cleavage are present in MCF-7 cells transfected with JAK2siRNA. These pre-clinical in vitro studies provide a mechanistic rationale to why high circulating levels ·()~IGF~I may seriously impact the progression of breast cancer and its response to hormonal tlierap~1 • and why the efficacy of hormonal therapy of breast cancer can be significantly improved · by simultaneously targeting these signaling pathway.