Cellular Metabolism of Estradiol in Models for Select Molecular Subtypes of Clinical Breast Cancer

Abstract

The mitogenic ovarian steroid hormone 17β-estradiol (E 2 ) is associated with progression of Estrogen Receptor Positive (ER + ) breast cancer, and ER represents a major therapeutic target for endocrine therapy. In addition to the ER dependent signal transduction, cellular oxidative metabolism of the ER ligand E 2 generates several metabolites with pleotropic growth modulatory effects on breast cancer cells, providing valuable leads for novel therapeutic approach. The molecular classification of clinical breast cancer has defined cancer subtypes based on differential expression of the genes for hormones and growth factor receptors, thereby facilitating subtype targeted therapeutic interventions. However, de novo or acquired resistance to conventional endocrine and targeted small molecule based treatment limits the therapeutic efficacy and promotes therapy resistant disease progression. These aspects emphasize the need for identification of new efficacious non-toxic lead compounds. The present review summarizes critical experiments conducted to i) develop and optimize human tissue derived cell culture models for select molecular subtypes of clinical breast cancer, ii) determine the status of homeostatic growth control, cellular metabolism of 17β-estradiol (E 2 ) and cancer risk in the developed models, and iii) evaluate the therapeutic efficacy and identify possible mechanisms of action of select herbal extracts/phyto-chemical. Additionally, this review discusses the evidence for the role of E 2 metabolism in breast carcinogenesis and therapy. The data generated from the cell culture experiments demonstrate that the models for select molecular sub-types exhibit aberrant hyperproliferation, altered cellular metabolism of E 2 and enhanced cancer risk. Select mechanistically distinct herbal extracts and natural phyto-chemical at their respective maximum cytostatic concentrations modulate cellular metabolism of E 2 favoring generation of anti-proliferative metabolites and inhibit anchorage independent growth, thus reducing cancer risk. Collectively, these data validate the present mechanism based cell culture approach to identify and prioritize novel efficacious lead compounds for subtype targeted therapy of clinical breast cancer.

Putative cancer-initiating stem cells in cell culture models for molecular subtypes of clinical breast cancer

“…In addition, contrary to the non-tumorigenic control cells, the breast carcinoma-derived cells appeared to have retained an enhanced risk for tumor development, as indicated by their ability to exhibit AI growth in vitro and tumor development in vivo following subcutaneous transplantation. Thus, AI growth represents a specific and sensitive in vitro surrogate biomarker for cancer risk (13,(17)(18)(19)(20).…”

“…, palpable tumors following subcutaneous transplantation; AI, anchorage-independent; MCF-7, Michigan Cancer Foundation-7; HER, human epidermal growth factor receptor. Data has been published previously (17,19). Table I.…”

“…The data summarized in Table I (17,19) compare the values obtained for a series of quantitative biomarker end points measured in non-tumorigenic 184-B5 cells vs. breast cancer-derived MCF-7, 184-B5/HER and MDA-MB-231 cells. The tumorigenic cells exhibited a ≥55% reduction in population doubling time, 19-47% increase in saturation density, 39-74% reduction in the G 1 :S+G 2 /M ratio and 7.0-9.5 fold increase in the S+G 2 /M:sub G 0 ratio.…”

“…The tumorigenic cells exhibited a ≥55% reduction in population doubling time, 19-47% increase in saturation density, 39-74% reduction in the G 1 :S+G 2 /M ratio and 7.0-9.5 fold increase in the S+G 2 /M:sub G 0 ratio. Additionally, unlike the non-tumorigenic 184-B5 cells, the tumorigenic cells exhibited AI growth in vitro and retained their tumor development ability in vivo (Table II) (17,19). , palpable tumors following subcutaneous transplantation; AI, anchorage-independent; MCF-7, Michigan Cancer Foundation-7; HER, human epidermal growth factor receptor.…”