Abstract
Despite early detection through the use of mammograms and aggressive intervention, breast cancer (BC) remains a clinical dilemma. BC can resurge after >10 years of remission. Studies indicate that BC cells (BCCs) with self-renewal and chemoresistance could be involved in dormancy. The majority of studies use in vitro, two-dimensional (2-D) monolayer cultures, which do not recapitulate the in vivo microenvironment. Thus, to determine the effect of three-dimensional (3-D) microenvironment on BCCs, this study fabricated tissue engineering scaffolds made of poly (ε-caprolactone) (PCL) having aligned or random fibers. Random and aligned fibers mimic, respectively, the random and highly organized collagen fibers found in the tumor extracellular matrix. Chemoresistant BCCs were obtained by treating with carboplatin. Western blot analysis of carboplatin resistant (treated) MDA-MB-231 (highly invasive, basal-like) and T47D (low-invasive, luminal) BCCs showed an increase in Bcl-2, Oct-4 and Sox-2, suggesting protection from apoptosis and increase in stem-like markers. Further studies with MDA-MB-231 BCCs seeded on the scaffolds showed little to no change in cell number over time for non-treated BCCs whereas on tissue culture polystyrene (TCP), non-treated BCCs displayed a significant increase in cell number at days 4 and 7 as compared to day 1 (p<0.05). Treated BCCs did not proliferate on TCP and the fibrous scaffolds. Little to no cyclin D1 was expressed for non-treated BCCs on TCP. On fibrous scaffolds, non-treated BCCs stained for cyclin D1 during the 7-day culture period. Treated BCCs expressed cyclin D1 on TCP and fibrous scaffolds during the 7-day culture period. Proliferation, viability and cell cycle analysis indicated that this 3-D culture prompted the aggressive BCCs to adopt a dormant phenotype, while the treated BCCs retained their phenotype. The findings indicate that random and aligned fibrous PCL scaffolds may provide a useful system to study how the 3-D microenvironment affects the behavior of BCCs.
Highlights
In the United States, breast cancer is the most prevalent cancer and the second most common cause of cancer death among women
Further studies with MDA-MB-231 BC cells (BCCs) seeded on the scaffolds showed little to no change in cell number over time for non-treated BCCs whereas on tissue culture polystyrene (TCP), non-treated BCCs displayed a significant increase in cell number at days 4 and 7 as compared to day 1 (p
Our results showed that the treated BCC population of cells was highly enriched with cells expressing CD44/CD24 markers
Summary
In the United States, breast cancer is the most prevalent cancer and the second most common cause of cancer death among women. In the absence of surgery, ionizing radiation and chemotherapeutic agents are the frontline therapies for the local control of breast cancer. With these non-surgical treatments, the principal issue becomes the lack of specificity for cancer cells alone, the cytotoxic effects on normal healthy cells limit both therapies. Recent studies have reported that another issue concerning radiation and chemotherapeutic agents is that cancer stem (tumor-initiating) cells remain dormant and acquire resistance to these conventional therapies [4,5,6,7]. BCSCs are described to have the capacity for long-term self-renewal, to transition to a dormant phenotype and resist existing therapeutic agents such as carboplatin, and initiate distant metastatic disease [10, 11]. A better understanding of the mechanism of dormancy is needed to isolate, identify and treat these cells [5, 11, 15,16,17,18,19] [20, 21] [22,23,24,25,26,27,28,29,30,31,32,33]
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