Triple-negative breast cancer (TNBC) is the most destructive form of breast cancer. TNBC lacks the expression of three receptors: estrogen alpha, progesterone and human epidermal growth factor 2, also called HER2.1 About 1 million women are diagnosed with breast cancer every year globally. Out of these diagnosed cases of breast cancer, 170,000 cases are diagnosed with the triple-negative phenotype (ER‑/PR-/HER2-). TNBC has the highest prevalence in premenopausal African American women. According to a recent report, 39% of all African American premenopausal women with breast cancer are diagnosed with TNBC. The occurrence of TNBC is much less in non-African American women, about 15%.2

Currently Available Treatment for TNBC

Due to its special molecular features, triple-negative breast cancer is sensitive to neither targeted therapy with trastuzumab nor endocrine therapy. There is no standard treatment regimen for the treatment of TNBC. Currently, the primary treatment method for TNBC is chemotherapy.3 Lack of targeted medications for TNBC and higher chances of TNBC recurrence have caused an extremely high number of deaths due to triple-negative breast cancer. Potent anticancer effects were seen in the subset of TNBCs that expressed estrogen receptor beta (ERβ) due to the ligand-mediated activation of ERβ.1

ERβ is a well-identified tumor suppressor that is expressed in 30% of TNBC tumors providing better patient outcomes.1 Research carried out by Dr. Hawse, a biologist at the Mayo Clinic, has demonstrated that estradiol effectively stops the growth of TNBC tumors that express ERβ. Estradiol usually promotes the growth of cancer cells in tumors that express estrogen receptor alpha (ERα); however, it has an opposite effect in TNBC tumors, i.e., it is able to inhibit the growth of TNBC in the presence of ERβ.4

Estradiol as a Ray of Light

Dr. Hawse and his colleagues from the Mayo Clinic’s research team discovered a potential mechanism by which estradiol provides anticancer effects in TNBC. The team found that estradiol stimulates the expression of a protein group called “cystatins” once it binds with the ERβ in TNBC. The cystatins exhibit a tumor-suppressing effect on the neighboring as well as distant cancer cells. The cystatins inhibit the canonical transforming growth factor β – TGFβ – signaling and suppress the metastatic phenotypes in vitro as well as in vivo. A phase II clinical trial will soon be open by the Translational Breast Cancer Research Consortium and the researchers at Mayo Clinic to test the efficacy of estradiol in metastatic TNBC that expresses ERβ.4

According to Matthew Goetz, a medical oncologist, and Dr. Hawse, estradiol is approved as a breast cancer treatment by the Food and Drug Administration and is normally used in women with ERα positive breast cancer that has become resistant to standard treatments. They say it would be interesting to study if estradiol can be repurposed as a new treatment for TNBC that expresses ERβ. This data shows the activity of cystatins in repressing the progression of breast cancer and highlights the importance of ERβ-targeted medications to treat TNBC. The study was funded by a specialized program of research excellence in breast cancer by the National Cancer Institute at Mayo Clinic (P50 CA116201) and the Eisenberg Foundation.4


  1. Reese JM, Bruinsma ES, Nelson AW, et al. ERβ-mediated induction of cystatins results in suppression of TGFβ signalling and inhibition of triple-negative breast cancer metastasis. PNAS. 2018 October 9;115(41):E9580-E9589.
  2. Ismail-Khan R, Bui MM. A review of triple-negative breast cancer. Cancer Control. 2010 Jul;17(3):173-176.
  3. Shi X, Wang L. Treatment for triple-negative breast cancer. Chin Ger J Clin Oncol. 2012 Sep;11(9):539-543.
  4. Science Daily. New potential treatment for one type of triple-negative breast cancer  [Updated Oct 4, 2018].