All cancers are clonal and represent the progeny of a single cell. The unclear point is which clonogenic cells within the tumor clone possess tumor-initiating cell (T-IC) function and are capable of maintaining tumor growth. Stem cells have the ability to divide almost indefinitely. The division can give rise to a new stem cell as well as differentiated cells of the tumor. Breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Among them, the breast cancer stem cell is important for regrowth of tumor and metastasis. Granulocyte-colony stimulating factor (G-CSF) stimulates the pluripotent stem cell beside neutrophil precursors. Breast cancer stem cells which have not been characterized totally may carry the almost identical antigens with hematopoietic stem cell. The dose-intense therapies with the addition of G-CSF in the adjuvant treatment of breast cancer improved clinical outcomes significantly. Presence of micrometastasis in bone marrow of the breast cancer patients is predictor of relapse free survival and important prognostic factor. Actually, breast cancer stem cells in the thousands of micrometastatic cancer cells have the capacity to repopulate and metastasise. We hypothesize that G-CSF use in adjuvant treatment of breast cancer may activate and repopulate these dormant breast cancer stem cells besides its stimulation on blood stem cells. So activated breast cancer stem cells become chemosensitive to cell-cycle specific various chemotherapeutic agents. Improvement in overall survival in operable breast cancer patients having been treated by dose-dense therapies may also be explained by this mechanism.

Antineoplastic Agents↗

PubMed2004

Adjuvant targeted therapy with trastuzumab may decrease metastatic capacity in specific group of oropharyngeal cancer patients: downregulation of E-cadherin-catenin complex by cooperative effect of erbB-2 and human papillomavirus type 16 E6/E7 protooncogenes.

Human papillomavirus (HPV) type 16 is causally associated with a subset of oral cancers, predominantly those cancers arising in the oropharynx (OP). Increased HPV16 E6 and E7 oncogene expressions are responsible for the malignant transmission in these cancers. ErbB-2 is the family member most closely implicated in human cancer, where it is overexpressed in about 30% of carcinomas including head and neck squamous cell carcinoma. Coexpressions of E6/E7 and ErbB-2 downregulate E-cadherin and catenin expression, therefore induces metastatic process. Trastuzumab is a humanized monoclonal antibody that recognizes the ErbB-2 protein receptor and breakthrough in the treatment of metastatic breast cancer in combination with chemotherapeutic agents. This antibody is also in clinical testing for adjuvant treatment of breast cancer. We propose that trastuzumab as an adjuvant treatment may decrease process of tumor metastasis in oropharyngeal cancer patients who completed primary treatment (surgery and/or radiotherapy) and show expression of both HPV16 E6/E7 and erbB-2 oncoproteins. In vitro and in vivo studies with trastuzumab in these subgroup of patients may support our hypothesis.

Antibodies, Monoclonal↗

PubMed2004

DNA methylation inhibitor, procainamide, may decrease the tamoxifen resistance by inducing overexpression of the estrogen receptor beta in breast cancer patients.

Estrogen is the main stimulant in the development and growth of breast cancer. The estrogen receptor antagonist tamoxifen has been mainstay of hormonal therapy. Although tamoxifen has been an effective adjuvant therapy, approximately 30% of patients treated with this agent still die within 10 years of follow-up treatment, and relapses can occur for > or = 20 years following therapy. However, the underlying cause of treatment failure in many breast cancer patients receiving tamoxifen is resistance to tamoxifen. ERbeta may influence estrogen action through the ERalpha pathway and the hormone refractoriness of breast cancer. ERbetacx, the carboxy terminal splicing variant of ERbeta, has been considered a dominant repressor of ERalpha function, because ERbetacx inhibits transcriptional activity of ERalpha rather than ERbeta wild type (wt). Tamoxifen responders tended to exhibit a lower ratio of ERbetacx to ERbetawt than non-responders. Induction of ERbeta reduces growth of exponentially proliferating cells. Since the promoter region of ERbeta is rich in CpG dinucleotides, loss of expression of ERbeta observed in some tumours could be due to aberrant methylation of CpG islands. Treatment of ERbeta-negative cell lines with DNA methyl transferase inhibitors restored ERbeta expression, providing experimental evidence that silencing of ERbeta in breast carcinomas could be due to promoter hypermethylation. Procainamide, used for cardiac arrhythmias, has been proposed as being a non-nucleoside inhibitor of DNA methylation and also demthylates and reactivate tumor suppressor genes in breast cancer cell lines. Therefore, concomitant use of procainamide with tamoxifen in ERalpha-positive and ERbeta-negative breast cancers may increase the tamoxifen response. Procainamide, given orally may also be used in breast cancer patients who developed resistance during the tamoxifen treatment. In vivo and in vitro studies evaluating effectiveness of concomitant use of procainamide and tamoxifen in tamoxifen resistant and ERbeta-negative breast cancer may further support our hypothesis.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Possible interaction between activator protein-1 and proto-oncogene B-cell lymphoma gene 6 in breast cancer patients resistant to tamoxifen.

About 75% of breast tumors are positive for the estrogen receptor (ER) or progesterone receptor (PgR) or both, and estrogen is the main stimulant in the development and growth of these tumors. Tamoxifen, an estrogen receptor antagonist has been endocrine treatment for hormone-sensitive breast cancer for more than 20 years. However, the underlying cause of treatment failure in many breast cancer patients receiving tamoxifen is resistance to tamoxifen. The mechanisms of tamoxifen and the molecular events responsible for resistance to tamoxifen are not fully understood. Two ER subtypes, ERalpha and ERbeta, activate the Activator Protein-1 (AP-1) response elements, and through interactions between ERs and the AP-1 transcription factors c-fos and c-jun, these transcription factors regulate the genes involved in many cellular processes, including proliferation, differentiation, cell motility, and apoptosis. Thus, the interaction between ERs and AP-1 could be important clinically and could have bearing on the response to tamoxifen. Tamoxifen acts as an agonist on genes under the control of an AP-1 response elements when ERalpha or ERbeta is expressed. AP-1 blockade suppresses mitogenic signals from multiple different peptide growth factors as well as estrogen, and inhibits the growth of MCF-7 breast cancer cells both in vitro and in vivo. Tamoxifen actually activate the AP-1 transcription factor. Increased AP-1 activity in breast cancer cells can lead to tamoxifen resistance. The proto-oncogene B-cell lymphoma gene 6 (BCL-6) has been characterized as a regulator of B-lymphocyte growth and development. BCL-6 is also expressed in the mammary epithelium in nonpregnant animals and during early pregnancy and is expressed in 68% of histologically high-grade ductal breast carcinomas, which are clinically the most aggressive. BCL-6 is a potent repressor of transcriptional activity mediated by AP-1 factors. We hypothesize that increased BCL-6 in breast cancer cells might block tamoxifen resistance by repressing AP-1, eventually resulting in apoptosis. We also suggest that BCL-6 expression must be analyzed in ER-positive breast cancer patients and the results must be correlated with predictive and prognostic factors and survival.

Antineoplastic Agents↗