Heregulin and retinoids synergistically induce branching morphogenesis of breast cancer cells cultivated in 3D collagen gels.
C-erbB and retinoid receptor signaling control mammary epithelial cell proliferation, differentiation, and morphology. Here, we examined the morphogenetic activities of c-erbB specific ligands such as heregulin and of retinoids on non-malignant (primary, MTSV1-7) and malignant (T47D, SKBR-3) human mammary epithelial cells (HMEC) cultivated in 3D collagen type I gels. These cells are positive for both c-erbB and retinoid receptors. Non-malignant primary HMEC spontaneously formed branched structures in collagen, whereas SV40 large T antigen-immortalized non-tumorigenic MTSV1-7 spontaneously formed balls and required heregulin or retinoid X receptor alpha-selective retinoid Ro 25-7386 for branching, which was further stimulated by combination of both types of agents. In malignant cells, heregulin alone induced ball formation and cooperated either with Ro 25-7386 (T47D) or with retinoic acid receptor alpha-selective AM580 (SKBR-3) for branching morphogenesis, which was accompanied by changes in the subcellular distribution of alpha(2)beta(1)-integrin and E-cadherin, and by down-regulation of c-erbB-2, -3, or -4. Heregulin and/or retinoids correspondingly increased the integrin-dependent adhesion of malignant cells to type I collagen. Our data demonstrate cooperative signaling of c-erbB and retinoid receptor pathways at the levels of morphogenesis and immunophenotypic differentiation.
Offterdinger
Martin
M
Signaling Networks Program, Clinical Division of Oncology, Department of Medicine I, University Hospital, Vienna, Austria.
Schneider
Sonja M
SM
Grunt
Thomas W
TW
D000954:Antigens, Surface / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002449:Cell Aggregation / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D016023:Integrins / Q000187:drug effects / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism* / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism*
D000954:Antigens, Surface; D015820:Cadherins; D016023:Integrins; D020890:Neuregulin-1; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D003094:Collagen; D066246:ErbB Receptors