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

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).