https://sorger.med.harvard.edu/wordpress/wp-content/uploads/2014/03/Sequential-application-of-anticancer-drugs-enhances-cell-death-by-rewiring-apoptotic-signaling-networks-Lee-Yaffe.pdf

Sequential Application of Anticancer Drugs Enhances Cell Death by Rewiring Apoptotic Signaling Networks

Triple-negative breast cancer—current status and future directions

Breast cancer is the most frequently diagnosed cancer in women and one of the leading causes of cancer death for women. Worldwide, over 1.3 million cases of invasive breast cancer are diagnosed, and more than 450,000 women die from breast cancer annually [1]. In the US, approximately 200,000 cases of invasive breast cancer and 50,000 cases of in situ breast cancer will be diagnosed annually, and more than 40,000 women die from breast cancer each year – second only to lung cancer [2]. The mortality due to breast cancer has been declining in the US since 1990 [2]. The continuing decrease in mortality from breast cancer has been attributed to early detection due to screening, improved adjuvant therapy, and more recently to decreases in the incidence due to lowered rates of usage of hormone replacement therapy [3, 4]. Despite the decreased incidence and mortality, breast cancer remains a major cause of cancer mortality for women and accounts for 15% of all cancer deaths in women in the US [2].

Clinically, breast cancer can be divided into distinct subtypes that have prognostic and therapeutic implications. Breast cancer patients routinely have the expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER-2/Neu evaluated [5]. These markers allow classification of breast cancer tumors as hormone receptor positive tumors, HER-2/Neu amplified tumors, and those tumors which do not express ER, PR, and do not have HER-2/Neu amplification. The latter group is referred to as triple-negative breast cancer (TNBC) based on the lack of these three molecular markers. Generally, hormone receptor expressing breast cancers have a more favorable prognosis than either those with HER-2/Neu amplification or those that are triple-negative [5]. While all breast tumor types may be treated with chemotherapy, therapeutic options in both early and late stage breast cancer are affected significantly by the expression of these three markers. Tumors that express ER and PR are treated with agents that interfere with hormone production or action [5]. Tumors that have amplified HER-2/Neu are treated with agents that inhibit HER-2/Neu [5]. These targeted therapies are the mainstay of the successful outcomes seen in hormone receptor positive and HER-2/Neu amplified tumors. Both early stage and advanced TNBC tumors are treated with predominantly chemotherapy [5].

TNBC represents approximately 10–15% of all breast cancers and patients with TNBC have a poor outcome compared to the other subtypes of breast cancer [6]. Interestingly, the incidence of TNBC in African American women is two to three times higher than other ethnic groups, although the reason for this has not been elucidated [6, 7]. Given the lack of validated molecular targets and the poor outcome in patients with TNBC, there is a clear need for a greater understanding of TNBC at all levels and for the development of better therapies.

Cancer cell lines have proved useful in laboratory and preclinical investigations since the first cell line was established more than 50 years ago [8]. For example, the anti-HER-2/Neu 4D5 mouse monoclonal antibody (which was humanized to create trastuzumab) had anti-tumor effects as a single agent and acted synergistically with chemotherapeutic agents in breast cancer cell lines that had amplified HER-2/Neu but showed no effect in cell lines lacking amplified HER-2/Neu [9–12]. These results formed the basis for clinical trials of trastuzmab and predicted the outcomes of these clinical trials. Similarly, preclinical studies using xenografts of a hormone receptor expressing breast cancer cell line have accurately predicted the outcomes of clinical trials comparing aromatase inhibitors to tamoxifen and to the combination of tamoxifen and aromatase inhibitors [13]. In this review, we will describe triple negative breast cancer cell lines and discuss their utility and the limitations of these cell lines in the investigation of TNBC (mindful of Harry Callahan’s admonition cited above).

Triple negative breast cancer cell lines: One tool in the search for better treatment of triple negative breast cancer

Decades of research in molecular oncology have brought about promising new therapies which are designed to target specific molecules which promote tumor growth and survival. The epidermal growth factor receptor (EGFR) is one of the first identified important targets of these novel antitumor agents. Approximately half of cases of triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) overexpress EGFR. Thus, EGFR inhibitors for treatment of breast cancer have been evaluated in several studies. However, results so far have been disappointing. One of the reasons for these unexpected results is the lack of biomarkers for predicting which patients are most likely to respond to EGFR inhibitors. Recent studies have shown that EGFR and its downstream pathway regulate epithelial-mesenchymal transition, migration, and tumor invasion and that high EGFR expression is an independent predictor of poor prognosis in IBC. Further, recent studies have shown that targeting EGFR enhances the chemosensitivity of TNBC cells by rewiring apoptotic signaling networks in TNBC. These studies indicate that EGFR-targeted therapy might have a promising role in TNBC and IBC. Further studies of the role of EGFR in TNBC and IBC are needed to better understand the best way to use EGFR-targeted therapy—e.g., as a chemosensitizer or to prevent metastases—to treat these aggressive diseases.

Role of epidermal growth factor receptor in breast cancer

Purpose
Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors comprising various breast cancers simply defined by the absence of estrogen receptor, progesterone receptor and overexpression of human epidermal growth factor receptor 2 gene In this review, we discuss the epidemiology, risk factors, clinical characteristics and prognostic variables of TNBC, and present the summary of recommended treatment strategies and all other available treatment options

An Overview of Triple-Negative Breast Cancer

Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer

Src: a potential target for the treatment of triple-negative breast cancer

The aim of this study was to investigate the effect of lapatinib, a selective inhibitor of EGFR/HER2 tyrosine kinases, on pancreatic cancer cell lines both alone and in combination with chemotherapy. Two cell lines, BxPc-3 and HPAC, displayed the greatest sensitivity to lapatinib (IC50 < 2 μM). Lapatinib also demonstrated some activity in three K-Ras mutated pancreatic cancer cell lines which displayed resistance to erlotinib. Drug effect/combination index (CI) isobologram analysis was used to study the interactions of lapatinib with gemcitabine, cisplatin and 5’deoxy-5’fluorouridine. Concentration-dependent anti-proliferative effects of lapatinib in combination with chemotherapy were observed. To evaluate the potential effect of lapatinib in pancreatic cancer tumours, and to identify a subset of patient most likely to benefit from lapatinib, expression of EGFR and HER2 were investigated in 72 pancreatic cancer tumour specimens by immunohistochemistry. HER2 membrane expression was observed in only 1 % of cases, whereas 44 % of pancreatic tumours expressed EGFR. Based on our in vitro results, lapatinib may provide clinical benefit in EGFR positive pancreatic ductal adenocarcinoma.

EGFR and HER2 inhibition in pancreatic cancer

In pre-clinical studies, triple-negative breast cancer (TNBC) cells have demonstrated sensitivity to the multi-targeted kinase inhibitor dasatinib; however, clinical trials with single-agent dasatinib showed limited efficacy in unselected populations of breast cancer, including TNBC. To study potential mechanisms of resistance to dasatinib in TNBC, we established a cell line model of acquired dasatinib resistance (231-DasB). Following an approximately three-month exposure to incrementally increasing concentrations of dasatinib (200 nM to 500 nM) dasatinib, 231-DasB cells were resistant to the agent with a dasatinib IC50 value greater than 5 μM compared to 0.04 ± 0.001 µM in the parental MDA-MB-231 cells. 231-DasB cells also showed resistance (2.2-fold) to the Src kinase inhibitor PD180970. Treatment of 231-DasB cells with dasatinib did not inhibit phosphorylation of Src kinase. The 231-DasB cells also had significantly increased levels of p-Met compared to the parental MDA-MB-231 cells, as measured by luminex, and resistant cells demonstrated a significant increase in sensitivity to the c-Met inhibitor, CpdA, with an IC50 value of 1.4 ± 0.5 µM compared to an IC50 of 6.8 ± 0.2 µM in the parental MDA-MB-231 cells. Treatment with CpdA decreased p-Met and p-Src in both 231-DasB and MDA-MB-231 cells. Combined treatment with dasatinib and CpdA significantly inhibited the growth of MDA-MB-231 parental cells and prevented the emergence of dasatinib resistance. If these in vitro findings can be extrapolated to human cancer treatment, combined treatment with dasatinib and a c-Met inhibitor may block the development of acquired resistance and improve response rates to dasatinib treatment in TNBC.

/pdf/dasatinib-treatment-increases-sensitivity-to-c-met-3miwzw8cm0.pdf

Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells.

e14605 Background: Triple-negative breast cancers (TNBC) lack expression of oestrogen, progesterone, and are HER-2 normal. TNBC cell lines have displayed greater sensitivity to growth inhibition by...

B. Corkery

Papers

Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer

Src: a potential target for the treatment of triple-negative breast cancer

EGFR and HER2 inhibition in pancreatic cancer

Dasatinib Treatment Increases Sensitivity to c-Met Inhibition in Triple-Negative Breast Cancer Cells.

Activity of dasatinib with chemotherapy in triple-negative breast cancer cells