Over‐expression of erbB‐2/neu is paralleled by inhibition of mouse‐mammary‐epithelial‐cell differentiation and developmental apoptosis

• Published in: International Journal of Cancer Vol. 85; no. 4; pp. 578 - 583
• Main Authors: Lazar, Hedvika, Baltzer, Anna, Gimmi, Claude, Marti, Andreas, Jaggi, Rolf
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York John Wiley & Sons, Inc 15.02.2000; Wiley-Liss
• Subjects: Animals; Apoptosis; Biological and medical sciences; Crosses, Genetic; Epithelial Cells - cytology; Epithelial Cells - physiology; erbB-2 gene; Female; Genes, erbB-2; Gynecology. Andrology. Obstetrics; Humans; Lactation; Male; Mammary gland diseases; Mammary Glands, Animal - cytology; Mammary Glands, Animal - growth & development; Mammary Glands, Animal - physiology; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Medical sciences; Mice; Mice, Transgenic; neu gene; neu protein; Pregnancy; Rats; Receptor, ErbB-2 - genetics; Tumors; Immunohistochemistry; Carcinoma; In situ; Rodentia; Transgenic animal; Gene overexpression; Malignant tumor; Hybridization; Cell differentiation; Gene expression; Carcinogenesis; Pathology; Mammary gland diseases; Vertebrata; Mammalia; Mouse; Animal; C-Onc gene; Mammary gland; Molecular biology; Protooncogene; Apoptosis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(20000215)85:4<578::AID-IJC21>3.0.CO;2-S

The erbB‐2/neu oncogene is frequently over‐expressed in many different tumors in humans, including those of breast and ovary. The oncogene encodes a receptor tyrosine kinase closely related to the epidermal‐growth‐factor receptor. We studied effects on differentiation and cell death of erbB‐2/neu during mammary‐gland development in transgenic mice expressing an activated, oncogenic rat erbB‐2/neu gene controlled by the mammary‐gland‐specific promoter from mouse‐mammary‐tumor virus (MMTV‐LTR). Transgenic animals develop mammary cancer after repeated pregnancies and lactation. We present evidence that over‐expression of erbB‐2/neu in these mice is restricted to tumor cells. Tumor cells fail to differentiate and express milk proteins such as β‐casein and whey acidic protein (WAP) during lactation. Epithelial‐cell apoptosis during normal involution is characterized by non‐random DNA degradation into oligonucleosomal fragments. Tumor cells were mostly refractory to this developmentally controlled programmed cell death. Distinct areas within tumors, however, showed spontaneous cell death as measured by in situ TUNEL staining that co‐localized with caspase‐3‐like activity. Our results indicate that the control of developmental cell death during involution is disturbed in erbB‐2/neu‐induced tumors although cell death and caspase activation can take place. Int. J. Cancer 85:578–583, 2000. © 2000 Wiley‐Liss, Inc.