|Montales, Maria Theresa -|
|Rahal, Omar -|
|Kang, Jie -|
|Rogers, Theodore -|
|Wu, Xianli -|
|Simmen, Rosalia -|
Submitted to: Carcinogenesis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 27, 2011
Publication Date: March 1, 2012
Citation: Montales, M.E., Rahal, O., Kang, J., Rogers, T., Prior, R.L., Wu, X., Simmen, R.C. 2012. Repression of mammosphere formation of human breast cancer cells by soy isoflavone genistein and blueberry polyphenolic acids suggests diet-mediated targeting of cancer stem-like/progenitor cells. Carcinogenesis. 33(3):652-660. Interpretive Summary: Modifiable factors such as diet and nutrition are implicated in the prevention and possible treatment of one of the leading causes of death in women, which is breast cancer. According to the cancer stem cell hypothesis, there is a population of cancer cells known as cancer stem and progenitor cells that initiates cancer formation. As stem cells, they have the ability to self-renew and propagate to more cancer cells. The study aims to determine the inhibitory effect of diet (particularly genistein-a major soy component and blueberry) on the cancer stem and progenitor cells. We utilized an assay wherein we were able to isolate the cancer stem cell population and treat this population of cells with genistein and blueberry extract. Results showed that diet can inhibit their growth and the possible mechanism is, by increasing the expression of genes involved in tumor suppression.
Technical Abstract: Mammary stem cells are undifferentiated epithelial cells which initiate mammary tumors and render them resistant to anticancer therapies, when deregulated. Diets rich in fruits and vegetables are implicated in breast cancer risk reduction, yet underlying mechanisms are poorly understood. Here, we addressed whether dietary factors selectively target mammary epithelial cells that display stem-like/progenitor subpopulations with previously recognized tumor-initiating potential. Using estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 human breast cancer cell lines and freshly isolated epithelial cells from MMTV-Wnt-1 transgenic mouse mammary tumors, we demonstrate that sera of adult mice consuming soy isoflavone genistein (GEN) or blueberry (BB) polyphenol-containing diets alter the population of stem-like/progenitor cells, as measured by their functional ability to self-renew and form anchorage-independent spheroid cultures in vitro at low frequency (1-2%). Serum effects on mammosphere formation were dose-dependently replicated by GEN (40 nM>2 µM) and targeted the basal stem-like CD44+/CD24-/ESA+ and the luminal progenitor CD24+ subpopulations in MDA-MB231 and MCF-7 cells. GEN inhibition of mammosphere formation was mimicked by the Akt inhibitor perifosine and was associated with enhanced tumor suppressor PTEN expression. By contrast, a select mixture of BB phenolic acids was only active in MDA-MD-231 cells and its CD44+/CD24-/ESA+ subpopulation, and this activity was independent of induction of PTEN expression. These findings delineate a novel and selective function of distinct dietary factors in targeting stem/progenitor cell populations in estrogen receptor-dependent and –independent breast cancers.