Therapeutic Targeting of Estrogen Receptor Beta in Triple Negative Breast Cancer

About 15 to 20 percent of women diagnosed with breast cancer worldwide have a form of the disease classified as triple negative breast cancer. Triple negative breast cancer (TNBC) is defined by a lack of expression of estrogen receptor alpha (ERα), the progesterone receptor and HER2 within tumor cells.

Effective and generally well-tolerated targeted therapies for patients with ERα-positive or HER2-positive disease include tamoxifen, aromatase inhibitors and trastuzumab. These therapies substantially reduce breast cancer recurrence and prolong survival.

However, for patients with triple negative breast cancer, prognosis is poor, and there are no targeted therapies available, leaving chemotherapy-based regimens as the only treatment option for these patients.

Despite the best treatment plans, five-year disease-free survival rates for women with triple negative breast cancer are about 50 percent, and nearly all patients who develop distant metastasis die of the disease.

Because of this, it's essential to identify novel drug targets and treatment strategies to more effectively treat, manage and hopefully cure triple negative breast cancer — something that researchers in the Mayo Clinic Breast Cancer SPORE are working to achieve.

This research project arose from the discovery that up to 30 percent of triple negative breast tumors express a second form of the estrogen receptor known as ERβ. Given that ERα remains the most common and important drug target for the treatment of breast cancer, the project team sought to determine if ERβ could serve as a novel drug target for triple negative breast cancer.

Through the development of multiple cell line and animal model systems, the Breast Cancer SPORE project team has demonstrated that estrogen, or drugs that specifically bind to and activate ERβ, elicit tumor suppressive effects in ERβ-positive triple negative breast cancer.

Other preliminary data suggest that the anti-cancer effects of ERβ seem to be mediated in part by a family of proteins known as cystatins, which are highly induced by ERβ in triple negative breast cancer cells.

The project team also has provided evidence that elevated cystatin levels lead to suppression of TGFβ signaling, a pathway known to drive triple negative breast cancer tumor progression, metastasis and resistance to chemotherapy regimens.

Hypothesis

Based on these data, the Breast Cancer SPORE project team hypothesizes that therapeutic activation of ERβ will result in clinical benefit for patients with ERβ-positive triple negative breast cancer by regulating a series of events that involves the induction of cystatins and suppression of canonical TGFβ signaling.

This project will culminate in a phase II study of estradiol in ERβ-positive triple negative breast cancer within the Translational Breast Cancer Research Consortium.

Project aims

This project has three aims:

  • Determine the role of cystatins and their impact on TGFβ signaling in mediating the anti-cancer effects of ERβ in TNBC and characterize the expression of these biomarkers in patients with triple negative breast cancer
  • Characterize the in vivo effects of estradiol and LY500307 (an ERβ specific drug) on ERβ-positive triple negative breast cancer patient-derived xenografts
  • Conduct a phase II clinical trial to elucidate the therapeutic efficacy of estradiol in patients with ERβ-positive triple negative breast cancer

Project investigators

Co-leaders of this Breast Cancer SPORE project are: