Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice - PubMed (original) (raw)

Fig. 2.

Histopathological analysis and immunophenotyping of mammary tumors. (A) Comparison of sections of lactating mammary glands (hematoxylin/eosin staining). (Magnification: ×20.) The specimens were from animals carrying the _Notch1_IC transgene, in which the Myc gene was either conditionally ablated (a and b) or functional (control) (c). The glands were isolated at 2 weeks postpartum after a first (a) or a second (b and c) pregnancy. After a first pregnancy, only miniscule and rare solid intraalveolar lesions occupying <1% of the surface area were observed in experimental animals (Inset). (Magnification: ×400.) After a second pregnancy, however, several small papillary lesions were detected (b, outlined). Although they are morphologically the same as those found in controls (c, outlined), the lesions of experimental mice were fewer and occupied collectively 4.2% of the alveolar surface area vs. 14.5% in controls (area of each lesion 0.21 ± 0.16 and 0.78 ± 0.45 mm2, respectively; P < 10−6). (B) Immunohistochemical staining (brown reaction product) for Notch1IC and Myc of WT lactating glands, and regressing and nonregressing tumors from mice with an MMTV-_N1_IC/Mycfl/fl/Wapcre genotype. (Magnification: ×400.) In contrast to the positive Notch1 immunoreactivity, normal lactating glands lack Myc immunostaining. However, there is highly positive Myc immunodetection in nonneoplastic epithelial cells of transgenic mice expressing N1IC (d Inset, same genotype as in Ac). In the regressing tumor (same as in Ab) there is strong nuclear staining for Notch1 in the neoplasm (b, arrow) and also in the nonneoplastic tissue (b, arrowheads). In contrast to a mosaic pattern of Myc immunoreactivity in the regressing tumor (e, arrows), the adjacent nonneoplastic tissue is Myc-negative (e, arrowheads). The Notch1IC-induced nonregressing carcinoma shows strong labeling for both Notch1 (c) and Myc (f). (C) Morphological patterns of nonregressing tumors developing in transgenic animals carrying MMTV LTR-driven _Notch1_IC (a) or Myc (b) or in bitransgenic mice expressing both oncogenes (c). (Magnification: ×400.) The histological architecture of Notch1IC-induced tumors is mostly papillary (a, arrows), whereas the Myc tumors are composed of small glandular elements and nests (b, arrowheads). The carcinomas of bitransgenic animals exhibit a hybrid architecture of interspersed small glandular elements (c, arrowhead) and large solid papillary structures (c, arrow). At the cellular level (Insets), the Myc tumors consist of large cells with large irregular nuclei and exhibit many apoptotic bodies (b Inset, arrow), whereas the Notch1 tumors have smaller cells with uniform nuclei and no apoptotic bodies (a Inset). (Magnification: ×1,000.) The cellular features of the cancers in bitransgenic mice resemble those of the Myc tumors, including the presence of apoptotic bodies (c Inset, arrow). (D) An example of a human breast cancer (serial sections) exhibiting strong nuclear immunoreactivity for both NotchIC (a) and Myc (b). (Magnification: ×400.) Histologically, this carcinoma has a growth pattern of small, solid, irregular nests (c, hematoxylin/eosin staining). (Scale bars: A, 1,000 μm; Aa Inset, B, C, and D, 50 μm; C Insets, 20 μm.)