Chemo Resistant Breast Cancer Biology Essay

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Breast cancer can be treated by surgery, radiation, hormones and chemotherapy. Although there is no resistance to surgery or radiation, reactivation of cancer stem cells may occur.

Hormonal therapy (anti- estrogen) is made by CDK10 silencing which increase ETS2 transcription of C-RAF causing activation in MAPK pathway and loss of tumor cell reliance upon estrogen signaling. Patients with ER-α positive tumors that express low CDK10 relapse early on Tamoxifen.

Patients with over expression of cyclin in breast cancer cells lead to acute anti- estrogen resistance. To overcome hormonal resistance, use growth factor receptor tyrosine kinase inhibitors alone or with anti- hormone agents.

Chemotherapy is a good method for treatment of breast cancer stem cells; however it may affect the normal cells. Fortunately, cancer stem cells are dependent on certain putative pathways as they use ATP to carry out certain biological processes, so it may be targeted for treatment. Treatment may also be done by monoclonal antibodies which target specific receptors as CD44, by blocking the angiogenesis, or it may be done by preparing liposomes containing Daunoruicin plus Quinarcrine targeting the mitochondria of breast cancer stem cells.

A recent study suggest that blockage of IL-8 receptor CXR1 by antibody or CXR1 inhibitor- like: Repertaxin- can cause apoptosis to tumor cells.

Role of cancer stem cells in breast cancer chemo resistance

The mechanisms of resistance of CSCs to chemotherapy are complex and not clarified but they may include over expression of ABC transporters, detoxification enzymes such as aldehyde dehydrogenase, low cell turnover rate or the ability to activate the DNA check point response.

CSCs rich in ABC transport proteins results in rapid and effective efflux of drugs outside the cells. [1] 

Breast cancer stem cells chemo resistance

Until the early 1990s, cancers were considered to be a mass of cells, all of which had equal potential to proliferate and initiate cancer .Then it's found that cancers often arise from normal tissues in the skin, gut and reproductive organs like breast where constant proliferation is required to ensure a continuous supply of newly differentiated cells. In the cancer tissue, this population of long-lived cells with extraordinary expansion potential has been called tumor-initiating cells or cancer stem cells (CSCs). Stem cells are biological cells found in all multicellular organisms, that can divide and differentiate into specialized cell types and can self-renew to produce more stem cells. In mammals, there are two broad types of stem cells embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which are found in various tissues stem cells and progenitor cells act as a repair system for the body, replenishing adult tissues. Cancer stem cells have proved that there are many similarities among the mechanisms of different forms of cancer. In some theories, cancer stem cells are believed to come from mutation in the stem cell but these studies are still under study.

Resistance to hormonal therapy (anti-estrogen)

It is identified that CDK10 is an important determent of this therapy as CDK10 silencing increases ETS2 driven transcription of C-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. The evidence of this observation is that patients with estrogen receptor α-positive tumors that express low level of CDK10 relapse early on Tamoxifen. [2] 

Resistance mainly noticed with estrogen receptor-negative / progesterone receptor negative and also studies showed that cells can switch from estrogen receptor-negative to estrogen receptor-positive. Over expression of cyclin in breast cancer cells leads to acute anti-estrogen resistance.

Using growth factor receptor tyrosine kinase inhibitors alone or in combination with anti-hormone agents to treat or even prevent hormonal resistant breast cancer is one of the important approaches undergoing clinical trials to overcome hormonal resistance. In vitro EGFR tyrosine kinase inhibitor Gefitinib (Iressa) suppresses proliferation of breast cancer cells in a dose-dependent manner. Gefitinib interferes with growth factor receptor and estrogen receptor cross-talk and to re-establish co-repressor complexes with tamoxifen-bound estrogen receptor on target gene promoters.

The phosphatidylinositol 3-kinase (PI3K/AKT) pathway interferes with estrogen receptor in breast tumors. A target protein for this enzyme is the molecular target of Rapamycin (mTOR), which can be suppressed using rapamycin analogues. [3] 

Strategies to overcome chemo resistant breast cancer

If the chemoresistant breast cancer cells are stem cells, so targeting them will be a logical & a good method for improving the treatment & the outcome of the breast cancer. If normal & cancer stem cells have the same biological pathways, it is difficult to achieve treatment without affecting the normal ones, but fortunately it appears that CSCs are more likely to be more dependent on certain putative pathways. [4] 

Cancer stem cells have over expression of ABC transporters which also called ATP binding cassette that utilize the energy of adenosine triphosphate (ATP) hydrolysis to carry out certain biological processes, so targeting them may be a strategy of choice in treatment.

Another strategy for treatment is to make monoclonal antibodies targeted against specific cellular surface molecules or receptors as CD44.

Another interesting strategy is to block the angiogenesis via blocking the vascular endothelial growth factors by some drugs like bevacizumab

Another attractive strategy, is to activate the apoptotic pathway by preparing liposomes containing daunoruicin plus quinacrine that targrt the mitochondria of the breast cancer stem cells that are approximately 98 nm . Liposomes increase the mitochondrial uptake of these drugs which activate the pro-apoptotic bax protein , subsequently increases the mitochondrial membrane potential & opens the mitochondrial permeability transition pores, releasing cytochrome c that activates catapase 9& 3 that activates apoptosis of breast cancer stem cells. [5] 

Another recent study suggests that the blockage of IL-8 receptor CXCR1 either by specific blocking antibody or by using a CXR1 inhibitor like repertaxin can selectively deplete the cancer stem cells in two human breast cancer cell line in vitro. It also causes apoptosis to the tumor cells via fasl /fas signaling which is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand receptor interactions play an important role in the regulation of the immune system and the progression of cancer. [6] 

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