Prevention of Breast Cancer and Therapy Resistance Using Novel Therapeutic Approaches
Abstract
Breast cancer is the most common cancer in women. The female hormone, estrogen, plays an important role in breast cancer progression and its action is mediated by two receptors, estrogen receptor-alpha (ERa), which promotes tumor growth, and ER-beta (ERb), which inhibits tumor growth. Current therapies for hormone-responsive breast cancers include antiestrogens and inhibitors estrogen production (aromatase inhibitor, AI). Although most patients respond to hormonal therapies, resistance develops and tumors recur in about 50% of patients. Breast tumors express low levels of ERb, and the high ratio between ERa and ERb levels provides the driving force for tumor cell growth and therapy resistance. Recent studies have also shown that a number of natural and synthetic compounds act as potent ERb agonists. Further, ERb agonists have potential to upregulate expression of ERb. With proven clinical safety, these drugs are currently being evaluated in clinical trials for the treatment of vasomotor symptoms (hot flashes), benign prostatic hyperplasia, and for the treatment of schizophrenia. The unique and novel significance of this proposal is to translate evolving scientific evidence on the functional role of ERb into a clinical strategy to prevent breast cancer, prevent or delay recurrence of hormone-resistant breast tumors, and resensitize therapy-resistant tumors to antiestrogen or aromatase therapies employing ERb-specific agonists with proven clinical safety profile. Our proposed therapeutic approach using ERb agonists has potential to overcome the current limitations associated with ERa-targeted endocrine therapy including limiting resistance and reducing undesirable treatment side effects. The proposed innovative work will help to demonstrate that ERb activation or its overexpression strongly inhibits ERa expression and activity and thus suppresses mechanisms by which ERa contributes to disease progression and resistance to endocrine therapies. Further, ERb agonist s ability to promote cancer cell death has the potential to prevent recurrence. Findings from this study will have immediate clinical impact and introduce a new paradigm of using ERb agonists to improve adjuvant endocrine therapy and provide a rationale to initiate novel preventive approaches to decrease the incidence of breast cancer. Since ERb agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERb agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for preventing and enhancing the survival of breast cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610294
Entities
People
- Rajeshwar Tekmal
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio