Breast cancer is the most commonly diagnosed cancer among U.S. women, and is the second leading cause of death among females. With one in eight women affected by breast cancer in their lifetime, researchers are scrambling to seek new diagnostic strategies and therapies to combat the disease and improve patient outcome.
A brand new study, performed by researchers from Brigham and Women’s Hospital (BWH) and the University of Miami Miller School of Medicine, has established that additional hormone receptors could be targeted to bolster existing treatment methods. In hormone-dependent breast cancer, current treatments focus on using medications that are capable of blocking estrogen from binding to intracellular estrogen receptors, situated inside the tumor cells; in turn, this prevents cancer cells from continuing to multiply and reduces the chance of their metastatic dissemination throughout the body.
First study author Sandro Santagata, of BWH Department of Pathology, and senior study author Tan A. Ince, of the University of Miami Miller School of Medicine, have now concluded that androgen and vitamin D receptors can, likewise, be sources of target. The latest findings were published in the Journal of Clinical Investigation, in a paper entitled Taxonomy of Breast Cancer Based on Normal Cell Phenotype Predicts Outcome.
The Discovery of New Receptor Profiles on Breast Cells
Breast cancers are clinically classified based upon the type of intracellular and extracellular receptors they bear; this includes the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Cells that possess estrogen receptors are defined as ER+. In addition, breast cancer cells that express progesterone receptors, also found within the interior of the cell, are defined as PR+, while the existence of HER2 – spanning the surface of the cell membrane – results in a HER2+ classification.
Ultimately, different positive/negative combinations of these receptors (ER +/-, PR +/-, HER2 +/-) help physicians determine the most effective treatment regimen. Estrogen positive cells can be treated using tamoxifen – an estrogen receptor blocker – thereby locking the cell in the dormant part of the cell cycle, preventing growth of the tumor. On the other hand, HER2 positive breast cancer can be treated using trastuzumab (a.k.a. Herceptin), which interferes with cell growth and division.
During the latest study, the research team investigated the “landscape” of breast cancer cells present within breast tissue, in the hope they might better characterize the subtypes of cells contained within. The group performed a comprehensive study of more than 15,000 normal breast cells, using immunohistochemical (IHC) staining, and encountered 11 previously “undefined” cell subtypes. The authors found that these 11 breast cell types could be placed into new hormonal differentiation groups, including HR0, HR1, HR2 and HR3. These categories were characterized by the expression of vitamin D, androgen and estrogen hormone receptors.
After making these startling new discoveries, the team began comparing the healthy breast tissue to over 3,000 human breast tumors, derived from previous cancer patients. Intriguingly, they found that the make-up of patient tumor cells were remarkably similar to one of the 11 normal subtypes. Furthermore, the researchers established that the response of a particular breast cancer sufferer to hormone treatment, along with their survival rate, was dependent upon which sub-group (HR0 to HR3) the cells from their tissue were categorized.
Future Treatments to Target Androgen and Vitamin D Receptors?
The new research study could have enormous implications for how breast cancers are classified, and could also pave the way for “triple hormone treatments” – a strategy that could be essential for better management of patients who are resistant to anti-estrogen treatments, such as tamoxifen. Triple hormone treatments – which would target estrogen, androgen, vitamin D and/or their receptors – could also prove more robust than single treatments. During a recent press release, Santagata discussed the potential opportunities their groundbreaking research may yield:
“There are many other interesting treatment opportunities that our findings may lead to… For instance, early data suggest that targeting androgen and vitamin D receptors in addition to standard chemotherapy may increase effectiveness, and may allow for lower doses of chemotherapy with the same effect.”
The findings are also useful for designing new treatments for breast cancer cells that do not possess HER2 or ER receptors. With this in mind, the researchers believe that the existing repertoire of targeted, anti-cancer therapies can be expanded by hunting for new drugs that affect the activity of androgen and vitamin D receptors.
Other studies have shown that vitamin D and calcium play a role in regulating cell proliferation and death, in both healthy cells and breast cancer cells; many researchers have conjectured vitamin D to be capable of offering anti-carcinogenic properties that protect against breast cancer. The active form of vitamin D can bind to vitamin D receptors and prevent cell proliferation; the pro-hormone can also prevent growth of new blood vessels that feed malignant breast cells the nutrients required for continued growth.
Ultimately, the authors believe their novel HR0 – HR3 classification could be used, in conjunction with the traditional clinical evaluation of breast cancer, to deliver healthcare improvements to patients. Santagata expressed his recent enthusiasm for the landmark findings:
“We have much more to learn about why normal breast cells are so diverse and how that information can help us better improve the diagnosis, prognosis and treatment of breast cancer patients.”
By James Fenner