We have studied effects of several nutrients on the proliferation of mammary ductal epithelial cells in C57BL/6J virgin female mice, using morphometry and [3H]dT in vivo labeling. A nutritional stress diet was given based on the AIN-76A semi-synthetic diet modified to contain four significant risk factors of a Western-style diet: high fat and phosphate and decreased calcium and vitamin D. The numbers of large, intermediate and terminal ducts and proliferating epithelial cells in mammary glands were assayed in control and stress diet groups. An increased number of mammary ducts and increased number of proliferating cells were found at the level of the small terminal ducts, a cancer-prone region in the mammary gland in the stress diet group compared to the control group after 20 weeks of diet administration. Thus, mammary terminal ductal hyperproliferation, expansion in the size of the proliferative epithelial cell compartment and excessive duplication of mammary ductal epithelial cells were found after this Western-style diet containing decreased dietary calcium and vitamin D. These changes are similar to those developing in colonic epithelium of mice maintained on the same diets and during chemically induced colonic carcinogenesis.
Background: Triple negative breast cancer (TNBC) lacks expressions of estrogen receptor-α (ER-α), progesterone receptor (PR) and amplified human epidermal growth factor receptor-2 (HER-2). Current treatment for TNBC includes anthracyclin, taxol and cisplatin-based conventional chemotherapy and survival pathway PARP, PI3K, AKT and mTOR selective targeted therapy. These treatments exhibit dose-limiting systemic toxicity and presence of drug resistant cancer stem cells, which highlight the need for identification of efficacious testable alternatives that are not toxic to non-tumorigenic cells. Dipsacus asperoides (DA) is a Chinese nutritional herb and its root represents a common ingredient in Chinese herbal formulations used in women for estrogen related health issues, osteoporosis and breast diseases. This study aims to investigate the growth inhibitory effects of DA, and to detect mechanisms for its efficacy.
Methods: Human mammary carcinoma derived triple negative MDA-MB-231 cell line represented the TNBC model. Non-fractionated aqueous extract from DA represented the test agent. Anchorage dependent growth, anchorage independent (AI) colony formation and cell cycle progression quantified growth inhibition. Western blot-based analysis for inhibition of RAS, PI3K and AKT and RB signaling identified mechanistic leads.
Results: Treatment with DA induced a dose dependent cytostatic growth arrest (IC50:15 µg/ml; IC90: 30 µg/ml), reduced AI growth and inhibited cell cycle progression via G2/M arrest. DA affected the RAS, PI3K, AKT and RB signaling pathways, and functioned as a natural inhibitor of cyclin dependent kinase 4/6. Cellular apoptosis paralleled increase in pro-apoptotic Caspase 3/7 activity.
Conclusion: These results demonstrate that DA inhibited growth, affected cell cycle progression, induced apoptosis and inhibited cancer cell survival pathways. This study validates a mechanism-based approach to identifying testable substitutes for secondary prevention/therapy of TNBC.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.