Abstract
PurposeEvidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors.MethodsImmunohistochemical staining(IHC) was used to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and proliferating cell nuclear antigen, and TUNEL was used to detect the apoptosis index. The significance of various variables in patient survival was analyzed using a Cox proportional hazards model. The percentage of BT-ICs in breast cancer cell lines and primary breast tumors was determined by ALDH1 enzymatic assay, CD44+/CD24− phenotype and mammosphere formation assay.ResultsALDH1 expression determined by IHC in primary breast cancers was associated with poor clinical response to neoadjuvant chemotherapy and reduced survival in breast cancer patients. Breast tumors that contained higher proportion of BT-ICs with CD44+/CD24− phenotype, ALDH1 enzymatic activity and sphere forming capacity were more resistant to neoadjuvant chemotherapy. Chemoresistant cell lines AdrR/MCF-7 and SK-3rd, had increased number of cells with sphere forming capacity, CD44+/CD24− phenotype and side-population. Regardless the proportion of T-ICs, FACS-sorted CD44+/CD24− cells that derived from primary tumors or breast cancer lines were about 10–60 fold more resistant to chemotherapy relative to the non- CD44+/CD24− cells and their parental cells. Furthermore, our data demonstrated that MDR1 (multidrug resistance 1) and ABCG2 (ATP-binding cassette sub-family G member 2) were upregulated in CD44+/CD24− cells. Treatment with lapatinib or salinomycin reduced the proportion of BT-ICs by nearly 50 fold, and thus enhanced the sensitivity of breast cancer cells to chemotherapy by around 30 fold.ConclusionsThese data suggest that the proportion of BT-ICs is associated with chemotherapeutic resistance of breast cancer. It highlights the importance of targeting T-ICs, rather than eliminating the bulk of rapidly dividing and terminally differentiated cells, in novel anti-cancer strategies.
Highlights
Chemotherapy is an important component in the treatment paradigm for breast cancers
We found that aldehyde dehydrogenase 1 (ALDH1) expression was associated with chemotherapeutic efficacy and clinical outcome of breast cancer patients, breast cancers containing a higher proportion of Breast tumor-initiating cells (BT-ICs) were more resistant to chemotherapy
To determine whether the number of BT-ICs is associated with chemotherapeutic efficacy, we performed immunohistochemical staining to examine ALDH1 expression in 192 cases of invasive ductal carcinomas of the breast obtained by core-needle biopsy prior to pre-operative neoadjuvant chemotherapy, and evaluated the expression level following the criteria of a previous study [15]
Summary
Chemotherapy is an important component in the treatment paradigm for breast cancers. We know that molecular mechanisms responsible for chemotherapeutic resistance of breast cancers are rather complicated, which involve overexpression of ATP-binding cassette transporters, anti-apoptotic factors [1] [2] and kinases for DNA repairing [3,4]. Targeting any single molecule is not sufficient to reverse chemotherapeutic resistance [5], suggesting that multiple molecular pathways may contribute to the sensitivity of breast cancer cells to chemotherapy. Breast tumor-initiating cells (BT-ICs) form spherical clusters (‘‘mammosphere’’) in suspension cultures due to their self-renewal capacity [8]. It has been shown that BT-ICs are more resistant to chemotherapy than non-BT-ICs due to multiple molecular mechanisms [10], including overexpression of ATP-
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