ABSTRACT Background Chemotherapy response is composed of drug resistance and sensitivity. Previously, we found that intratumoral heterogeneity of invasive ductal breast carcinoma not otherwise specified (IDBC NOS), presented by the different types of morphological structures (tubular, trabecular, solid, alveolar structures, and discrete groups of tumor cells) displaying architectural arrangements of tumor cells may influence on chemotherapy response (Zavyalova et al., 2008); however, the mechanism of this effect is unknown. Aim We aimed to analyze expression of the multidrug resistance (MDR) and chemosensitivity genes in the different types of morphological structures and their microenvironment of tumor in IDBC NOS. Materials and methods Tubular, trabecular, alveolar structures, and their microenvironment (local and distant) were isolated by laser microdissection PALM (Carl Zeiss, Gemany) from 10 um sections of FFPE breast tumor. The isolated and whole amplified cDNA (RNA) was used for analysis of the MDR (ABCB1, ABCC1, ABCC2, ABCC5, ABCG2, GSTP1, and MVP) and chemosensitivity (TOP1, TUBB3, and TYMS) genes by the real-time TaqMan PCR. Results As seen in Table 1, expression of the MDR and chemosensitivity genes was significantly different between both the studied types of morphological structures and their microenvironment. Moreover, we observed the interesting phenomenon consisting in the fact that different types of morphological structures and their local microenvironments are supplemented each other in expression of the MDR and chemosensitivity genes. Tubular structures had a significantly higher activity of the MDR and chemosensitivity genes in comparison with other types of morphological structures, whereas their microenvironment was fully inactive in respect of the expressing genes. In contrast, a low expression level of the MDR and chemosensitivity genes in alveolar structures was compensated by high activity of these genes in the surrounding microenvironment. Interestingly that trabecular structures displaying moderate expression of the analyzed genes had microenvironment with a similar level of activity of these genes. Conclusion Together, the data obtained demonstrates that within IDBC NOS tumor there are subclones of tumor cells and their specific microenvironment with different expression of chemotherapy response markers.The study was supported by the Russian Federation President Grant (MK-1259.2012.7) and grant of the OPTEK company.