الفهرس 
Molecular Biology of Breast CancerOnly 14 pages are availabe for public view
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Abstract
Breast cancer alone is expected to account for 27% of all new cancer cases among women
Our understanding of the biology of breast cancer is increasing steadily this allow field of personalized medicine to expand and this lead to more effective treatment of cancer .
Intracellular signaling thus translates cues from the extracellular environment, into appropriate cellular responses . One of the largest groups is tyrosine kinase group.
The tyrosine kinases in turn are divided into two large classes: Receptor and non-receptor TKs. The enzymatic activities of both types of TKs are under tight control; receptor tyrosine kinase include: HER family .PDGFR,VEGFR and IGF .
Interrupt TK signaling through neutralization of ligand, blockade of ligand binding, receptor internalization, and perhaps antibody-mediated cytotoxicity.
The approval of trastuzumab for use in metastatic breast cancer marked a breakthrough in the understanding of the biology of the disease
Trastuzumab used in the adjuvant setting significantly prolongs both PFS and OS in patients with HER-2 overexpressing breast cancer .
The addition of lapatinib to capecitabine was associated with a 51% reduction in the risk of disease progression.
Targeting the epidermal growth-factor receptor (EGFR) family is a main strategy for drug development in the treatment of metastatic breast cancer. One approach is to inhibit the cross-talk among different EGFRs by inhibiting multiple receptors at once.
Second target is angiogenesis which provides an attractive therapeutic target
VEGF inhibition results from three main mechanisms: lignad sequestration via soluasble receptors or monoclonal antibodies (MAbs); receptor-blocking by soluble receptors or MAbs; or by indirect inhibition of growth factors (i.e. HER-2)
bevacizumab in combination with chemotherapy as first line treatment for patients with metastatic and locally recurrrent breast cancer result in the use of bevazuzumab have significant increase in PFS ,response rate and 1 year OS .
Preclinical and clinical findings suggest a potential role of some of these agents in specific settings:Gefitinib and Erlotinib are a oral EGFR TKI.
The ability to restore ER expression by targeting growth factor signaling would create an additional opportunity. Clinical and preclinical data that suggest an increased production of VEGF in breast cancer could contribute to anti-hormone resistance, combined modality treatment with VEGF signaling inhibitors and hormone-receptor antagonists offers potential for treating patients with hormone-positive breast cancers .
The growth factor family of epidermal growth factor (EGFR and HER2) are recognized to be implicated in the endocrine resistance through activation of mitogen-activated protein kinase/extracellular signal-related kinase and/or the phosphatidylinositol 3’-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway.
mTOR pathway plays a key role in tumorigenesis and that mTOR inhibition is a potentially important antitumor target .
Rapalogs may be more effective in combination with other anticancer agents, including chemotherapy and targeted therapies.
mTOR has been identified as a key kinase functioning downstream of PI3K/Akt, and thus its inhibition has emerged as a potentially important therapeutic target .
Results of a phase I trial of this combination in patients with MBC whose disease was stable or had progressed after 4 months with letrozole alone showed that it was well tolerated and active in this patient population .
An ongoing randomized, double-blind, placebo-controlled phase III trial (NCT00863655: Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole )(BOLERO-2) is evaluating everolimus in combination with exemestane in patients with estrogen-receptor positive locally advanced or metastatic breast cancer who are refractory to letrozole or anastrozole .
mTOR inhibitors have been found to be additive or synergistic with paclitaxel, carboplatin, cisplatin, vinorelbine, doxorubicin, and campthotecin. Compared with single agent therapy, the combination of rapamycin with chemotherapy enhances apoptosis in vitro and enhances antitumor efficacy in vivo .
In HER-2–positive breast cancer cell lines, trastuzumab has been shown to inhibit feedback-loop activation of Akt. This is especially notable as PTEN loss is a known mediator of trastuzumab resistance providing another rationale to use mTOR inhibitors to restore or enhance trastuzumab sensitivity
The development of target-based agents in breast cancer has been characterized up to now by rather few successes and several failures. As matter of fact, the target-based agents that have shown significant clinical activity in breast cancer patients up to now. Understand how the complex survival pathways interact, we can combine targeted agents rationally .