S74-3 New Strategies to Overcome Anti-Estrogen Resistance by Dual Targeting of Src and ER Signaling in Breast and Ovarian Cancer

Program: Symposia
Session: S74-Bench to Bedside: Cellular Signaling and Regulation of Steroid Receptor Function
Translational
Tuesday, June 18, 2013: 1:30 PM-3:00 PM
Presentation Start Time: 2:30 PM
Room 303 (Moscone Center)
Joyce M. Slingerland*
University of Miami Miller School of Medicine, Miami, FL
Talk Description:

Up to 60% of newly diagnosed breast and ovarian cancers express the estrogen receptor α (ER) protein. While breast cancers are often initially responsive to drugs that oppose estrogen action, both responsive breast cancers and most ovarian cancers invariably develop resistance to antiestrogens. Antiestrogens are used to treat positive breast cancers and cause p27-dependent G1 arrest in both breast and ovarian cancers. However, cross talk between estrogen-bound ER recruits and activates Src to mediate proteolysis of p27 and drive cell proliferation. Src is constitutively activated in a majority of both breast and ovarian cancers. Indeed in cancers. We have tested the anti-tumor efficacy of combined inhibition of both Src and either aromatase or ER in both breast and ovarian cancer models. Combined inhibition of both Src and ER signaling led to higher p27 levels and Ki67 in breast models, activation of autophagy in ovarian models, increased cell cycle arrest in both and greater antitumor efficacy in vivo. Notably, monotherapy with Src inhibitor, saracatinib, alone cause bypass activation of MEK/MAPK and PI3K/mTOR pathways in vivo suggesting further evaluation of combined targeted therapies may hold promise in clinical trials. Preliminary data from dual anastrozole and saracatinib therapy trials in ER positive breast cancer will be discussed.

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