Stem Cells: Their Role in Breast Cancer Development and Resistance to Treatment

A.      Nicolini; P.      Ferrari; M.      Fini; V.      Borsari; P.      Fallahi; A.      Antonelli; P.      Berti; A.      Carpi; P.      Miccoli

Abstract

About 20% of the total cells from primary breast tumors could generate palpable tumors in non-obese diabetic severe combined immunodeficient (NOD/SCID) immunocompromised mice. All the tumorigenic cells originate from a normal mammary stem cell. Human mammary stem cells are sensitive to oncogenic mutations and in mouse models they share similarities with breast cancer stem cells (BrCSCs). Tumorigenicity, invasion, progression and metastasization are further BrCSCs properties likely depending on their CD44+/CD24- phenotype. Local invasion and tumor metastasization seem to be facilitated by the epithelial to mesenchymal transition (EMT) program. This program may be reactivated from stable genetic alterations or through exposure of cancer cells to factors present in the surrounding micro-environment, or by an up-regulation of EMT-inducing transcription factors. One main explanation for resistance to treatment by cancer cells is that a rare subpopulation of cells in residual tumors with tumorigenic potential is intrinsically resistant to therapy. Consistent with this hypothesis, in human breast tumors, the subpopulation of tumor-initiating cancer cells with CD44high/CD24low cell surface-marker profile was found more resistant to cancer therapies (chemo, hormone and radiotherapy) than is the major population of more differentiated breast cancer cells. The reasons for CSC resistance to chemotherapy, hormonetherapy and radiotherapy also have been examined and they opened new scenarios for cancer therapy.

Keywords: Breast cancer, cancer stem cells, chemotherapy, hormonetherapy, radiotherapy, resistance, non-obese diabetic severe combined immunodeficient (NOD/SCID), tumorigenic cells, oncogenic mutations, Tumorigenicity, metastasization, epithelial to mesenchymal transition (EMT), transcription factors, murine mammary gland, ductal, alveolar, epithelial, myoepithelial cells, luminal cell, glycoprotein, metastatic potential, cytokines warrants, TGF-beta, signaling activity, CD44+, recombinant IL-8, ESA (epithelial specific antigen, carcinogenesis, Wnt, Notch, Hedgehog signaling, beta-catenin, melanoma, interleukin-2, hyaluron, osteopontin OPN, vascular endothelial growth factor (VEGF), chemokine, immuno-histochemical staining, mesenchymal-to-epithelial transition (MET), fibroblasts, Preferential resistance, paclitaxel, 5-flurouracil, docetaxel, doxorubicin plus, cyclophosphamide, multi-drug-resistant (MDR) proteins, ATP-binding cassette (ABC), endocrine therapy, endocrine resistance, trastuzumab, lapatinib, fulvestrant, moxifen, tamoxifen antagonism, progesterone, E-cadherin, kappaB, lymph nodes, disseminated tumor cells, vimentin