Tamoxifen (Tam) is the most frequently prescribed drug for breast cancer. Its effectiveness is limited, however, by the development of acquired resistance in most patients. Mechanisms for this acquired resistance are largely unknown, but their clarification would have profound clinical implications for new strategies to prevent, delay, or reverse the development of resistance. Using an in vivo model, we have found that one form of resistance is due to the acquired ability of tumors after chronic Tam therapy to be stimulated rather than inhibited by Tam; clinical observations also support this finding. How Tam could stimulate tumor growth after a prolonged period of growth suppression is unknown, though we have found that Tam-stimulated growth is not due to altered systemic or tumor metabolism of Tam. Nor is this form of resistance due to loss or mutation of the estrogen receptor (ER). We also found that Tam-stimulated tumor growth can be blocked by the pure steroidal antiestrogen ICl 182,780, which works by a different mechanism than Tam - this has led directly to a clinical trial by collaborators in England. Recent data suggest two hypotheses that we now propose to investigate to explain Tam-stimulated growth. First, ER contains two transcriptional activating regions, including a constitutively active albeit weak domain known as AF-1. It has been hypothesized that the agonist activity of Tam observed in some tissues may be due to enhanced AF-1 activity caused by tissue-specific factors that interact with ER. Second, ER can modify gene expression not only through the estrogen response element on target genes, but also by directly interacting with other transcription factors including a factor called AP-1. We have now found that Tam-stimulated tumor growth is associated with increased AP-1 activity, perhaps as a result of Tam- induced oxidant stress which is a potent inducer of AP-1. We therefore hypothesize that this increased AP-1 activity may result in tumor growth stimulation after chronic Tam treatment, so that anti-oxidant therapy may be able to delay the emergence of resistance. The following specific aims are proposed to address these two hypotheses. (1) We will determine whether Tam-stimulated growth is associated with increased ER AF-1 transcriptional activity, and then identify ER- interacting accessory proteins that may be involved. (2) We will determine whether Tam-stimulated growth is due to altered AP-1 activity as a result of oxidant stress. Then we will explore strategies to delay or prevent Tam-stimulated growth by anti-oxidant therapy. These studies should provide important new insights into mechanisms of tamoxifen resistance, and may thereby offer new strategies to be exploited in future clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
3P50CA058183-08S6
Application #
6575622
Study Section
Project Start
1999-08-30
Project End
2003-07-31
Budget Start
Budget End
Support Year
8
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Type
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Kaochar, Salma; Mitsiades, Nicholas (2018) A Novel Mechanism to Drive Castration-Resistant Prostate Cancer. Trends Endocrinol Metab 29:366-368
Bhat, Raksha R; Yadav, Puja; Sahay, Debashish et al. (2018) GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer. Breast Cancer Res Treat 170:279-292
Guarducci, Cristina; Bonechi, Martina; Benelli, Matteo et al. (2018) Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer. NPJ Breast Cancer 4:38
Rimawi, Mothaffar F; De Angelis, Carmine; Contreras, Alejandro et al. (2018) Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Res Treat 167:731-740
Sukumaran, Sujita; Watanabe, Norihiro; Bajgain, Pradip et al. (2018) Enhancing the Potency and Specificity of Engineered T Cells for Cancer Treatment. Cancer Discov 8:972-987
Hertz, D L; Kidwell, K M; Hilsenbeck, S G et al. (2017) CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study. Breast Cancer Res Treat 166:277-287
Yu, L; Liang, Y; Cao, X et al. (2017) Identification of MYST3 as a novel epigenetic activator of ER? frequently amplified in breast cancer. Oncogene 36:2910-2918
Guven, Adem; Villares, Gabriel J; Hilsenbeck, Susan G et al. (2017) Carbon nanotube capsules enhance the in vivo efficacy of cisplatin. Acta Biomater 58:466-478
Veeraraghavan, Jamunarani; De Angelis, Carmine; Reis-Filho, Jorge S et al. (2017) De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance. Breast 34 Suppl 1:S19-S26
Xu, Xiaowei; De Angelis, Carmine; Burke, Kathleen A et al. (2017) HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer. Clin Cancer Res 23:5123-5134

Showing the most recent 10 out of 306 publications