DOI: 10.1073/pnas.232711199. CEACAM1-4S, a cell–cell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture

CEACAM1-4S, a cell–cell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture

10.1073/pnas.232711199

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

In a 3D model of breast morphogenesis, CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) plays an essential role in lumen formation in a subline of the nonmalignant human breast cell line (MCF10A). We show that mammary carcinoma cells (MCF7), which do not express CEACAM1 or form lumena when grown in Matrigel, are restored to a normal morphogenic program when transfected with CEACAM1-4S, the short cytoplasmic isoform of CEACAM1 that predominates in breast epithelia. During the time course of lumen formation, CEACAM1-4S was found initially between the cells, and in mature acini, it was found exclusively in an apical location, identical to its expression pattern in normal breast. Lumena were formed by apoptosis as opposed to necrosis of the central cells within the alveolar structures, and apoptotic cells within the lumena expressed CEACAM1-4S. Dying cells exhibited classical hallmarks of apoptosis, including nuclear condensation, membrane blebbing, caspase activation, and DNA laddering. Apoptosis was mediated by Bax translocation to the mitochondria and release of cytochrome c into the cytoplasm, and was partially inhibited by culturing cells with caspase inhibitors. The dynamic changes in CEACAM1 expression during morphogenesis, together with studies implicating extracellular matrix and integrin signaling, suggest that a morphogenic program integrates cell–cell and cell–extracellular matrix signaling to produce the lumena in mammary glands. This report reveals a function of CEACAM1-4S relevant to cellular physiology that distinguishes it from its related long cytoplasmic domain isoform.

Bibliography

Kirshner, J., Chen, C.-J., Liu, P., Huang, J., & Shively, J. E. (2003). CEACAM1-4S, a cellâcell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture. Proceedings of the National Academy of Sciences, 100(2), 521â526.

Authors 5

Julia Kirshner (first)
Charng-Jui Chen (additional)
Pingfang Liu (additional)
Jie Huang (additional)
John E. Shively (additional)

References 40 Referenced 146

10.1016/0161-5890(79)90063-4
10.1016/S0955-0674(97)80114-7
10.1073/pnas.85.18.6959
10.1083/jcb.108.2.267
10.1128/mcb.13.2.1273-1282.1993
P Nollau, H Scheller, M Kona-Horstmann, S Rohde, F Hagenmuller, C Wagener, M Neumaier Cancer Res 57, 2354–2357 (1997). / Cancer Res by Nollau P (1997)
10.1177/002215549704500705
J Huang, J F Simpson, C Glackin, L Riethorf, C Wagener, J E Shively Anticancer Res 18, 3203–3212 (1998). / Anticancer Res by Huang J (1998)
10.1073/pnas.90.22.10744
J T Hsieh, W Luo, W Song, Y Wang, D I Kleinerman, N T Van, S H Lin Cancer Res 55, 190–197 (1995). / Cancer Res by Hsieh J T (1995)
S H Lin, Y S Pu Semin Oncol 26, 227–233 (1999). / Semin Oncol by Lin S H (1999)
10.1006/bbrc.1999.1443
10.1097/00005392-199909010-00085
10.1242/jcs.112.23.4193
10.1002/(SICI)1097-4652(199704)171:1<11::AID-JCP2>3.0.CO;2-K
10.1091/mbc.10.9.2817
10.1073/pnas.89.19.9064
10.1073/pnas.95.25.14821
10.1083/jcb.137.1.231
10.1016/S0959-8049(00)00062-9
10.1016/0304-3835(91)90093-W
10.1002/(SICI)1096-9896(199904)187:5<567::AID-PATH288>3.0.CO;2-J
10.1083/jcb.138.6.1379
10.1038/sj.cdd.4400404
10.1074/jbc.273.16.9357
M Rojas, A Fuks, C P Stanners Cell Growth Differ 1, 527–533 (1990). / Cell Growth Differ by Rojas M (1990)
10.1016/S0021-9258(18)52436-4
10.1016/0006-291X(92)90828-9
10.1038/sj.onc.1202935
T Kunath, C Ordonez-Garcia, C Turbide, N Beauchemin Oncogene 11, 2375–2382 (1995). / Oncogene by Kunath T (1995)
10.1016/0092-8674(95)90169-8
10.1074/jbc.M109110200
10.1016/S0014-5793(98)00222-1
10.1182/blood.V84.1.211.211
L Frangsmyr, V Baranov, F Prall, M M Yeung, C Wagener, S Hammarstrom Cancer Res 55, 2963–2967 (1995). / Cancer Res by Frangsmyr L (1995)
10.1083/jcb.96.4.1168
H Sun, S A Santoro, M M Zutter Cancer Res 58, 2224–2233 (1998). / Cancer Res by Sun H (1998)
10.1126/science.7531366
10.1016/S0002-9440(10)61725-7
10.1038/ncb0901-785

Dates

Type	When
Created	22 years, 7 months ago (Jan. 21, 2003, 5:51 p.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 9:07 a.m.)
Indexed	3 months, 1 week ago (May 19, 2025, 8:30 a.m.)
Issued	22 years, 7 months ago (Jan. 9, 2003)
Published	22 years, 7 months ago (Jan. 9, 2003)
Published Online	22 years, 7 months ago (Jan. 9, 2003)
Published Print	22 years, 7 months ago (Jan. 21, 2003)

Funders 0

None

BibTeX

@article{Kirshner_2003, title={CEACAM1-4S, a cell–cell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture}, volume={100}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.232711199}, DOI={10.1073/pnas.232711199}, number={2}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Kirshner, Julia and Chen, Charng-Jui and Liu, Pingfang and Huang, Jie and Shively, John E.}, year={2003}, month=jan, pages={521–526} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        5,
        19
      ]
    ],
    "date-time": "2025-05-19T12:30:14Z",
    "timestamp": 1747657814818
  },
  "reference-count": 40,
  "publisher": "Proceedings of the National Academy of Sciences",
  "issue": "2",
  "content-domain": {
    "domain": [
      "www.pnas.org"
    ],
    "crossmark-restriction": true
  },
  "published-print": {
    "date-parts": [
      [
        2003,
        1,
        21
      ]
    ]
  },
  "abstract": "<jats:p>\n            In a 3D model of breast morphogenesis, CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) plays an essential role in lumen formation in a subline of the nonmalignant human breast cell line (MCF10A). We show that mammary carcinoma cells (MCF7), which do not express CEACAM1 or form lumena when grown in Matrigel, are restored to a normal morphogenic program when transfected with CEACAM1-4S, the short cytoplasmic isoform of CEACAM1 that predominates in breast epithelia. During the time course of lumen formation, CEACAM1-4S was found initially between the cells, and in mature acini, it was found exclusively in an apical location, identical to its expression pattern in normal breast. Lumena were formed by apoptosis as opposed to necrosis of the central cells within the alveolar structures, and apoptotic cells within the lumena expressed CEACAM1-4S. Dying cells exhibited classical hallmarks of apoptosis, including nuclear condensation, membrane blebbing, caspase activation, and DNA laddering. Apoptosis was mediated by Bax translocation to the mitochondria and release of cytochrome\n            <jats:italic>c</jats:italic>\n            into the cytoplasm, and was partially inhibited by culturing cells with caspase inhibitors. The dynamic changes in CEACAM1 expression during morphogenesis, together with studies implicating extracellular matrix and integrin signaling, suggest that a morphogenic program integrates cell\u2013cell and cell\u2013extracellular matrix signaling to produce the lumena in mammary glands. This report reveals a function of CEACAM1-4S relevant to cellular physiology that distinguishes it from its related long cytoplasmic domain isoform.\n          </jats:p>",
  "DOI": "10.1073/pnas.232711199",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2003,
        1,
        21
      ]
    ],
    "date-time": "2003-01-21T22:51:47Z",
    "timestamp": 1043189507000
  },
  "page": "521-526",
  "update-policy": "http://dx.doi.org/10.1073/pnas.cm10313",
  "source": "Crossref",
  "is-referenced-by-count": 146,
  "title": "CEACAM1-4S, a cell\u2013cell adhesion molecule, mediates apoptosis and reverts mammary carcinoma cells to a normal morphogenic phenotype in a 3D culture",
  "prefix": "10.1073",
  "volume": "100",
  "author": [
    {
      "given": "Julia",
      "family": "Kirshner",
      "sequence": "first",
      "affiliation": [
        {
          "name": "Graduate School and Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; and School of Medicine, University of California at San Diego, La Jolla, CA 92093"
        }
      ]
    },
    {
      "given": "Charng-Jui",
      "family": "Chen",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Graduate School and Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; and School of Medicine, University of California at San Diego, La Jolla, CA 92093"
        }
      ]
    },
    {
      "given": "Pingfang",
      "family": "Liu",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Graduate School and Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; and School of Medicine, University of California at San Diego, La Jolla, CA 92093"
        }
      ]
    },
    {
      "given": "Jie",
      "family": "Huang",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Graduate School and Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; and School of Medicine, University of California at San Diego, La Jolla, CA 92093"
        }
      ]
    },
    {
      "given": "John E.",
      "family": "Shively",
      "sequence": "additional",
      "affiliation": [
        {
          "name": "Graduate School and Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010; and School of Medicine, University of California at San Diego, La Jolla, CA 92093"
        }
      ]
    }
  ],
  "member": "341",
  "published-online": {
    "date-parts": [
      [
        2003,
        1,
        9
      ]
    ]
  },
  "reference": [
    {
      "key": "e_1_3_3_1_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0161-5890(79)90063-4"
    },
    {
      "key": "e_1_3_3_2_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0955-0674(97)80114-7"
    },
    {
      "key": "e_1_3_3_3_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.85.18.6959"
    },
    {
      "key": "e_1_3_3_4_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.108.2.267"
    },
    {
      "key": "e_1_3_3_5_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1128/mcb.13.2.1273-1282.1993"
    },
    {
      "key": "e_1_3_3_6_2",
      "first-page": "2354",
      "volume": "57",
      "author": "Nollau P",
      "year": "1997",
      "unstructured": "P Nollau, H Scheller, M Kona-Horstmann, S Rohde, F Hagenmuller, C Wagener, M Neumaier Cancer Res 57, 2354\u20132357 (1997).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_7_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1177/002215549704500705"
    },
    {
      "key": "e_1_3_3_8_2",
      "first-page": "3203",
      "volume": "18",
      "author": "Huang J",
      "year": "1998",
      "unstructured": "J Huang, J F Simpson, C Glackin, L Riethorf, C Wagener, J E Shively Anticancer Res 18, 3203\u20133212 (1998).",
      "journal-title": "Anticancer Res"
    },
    {
      "key": "e_1_3_3_9_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.90.22.10744"
    },
    {
      "key": "e_1_3_3_10_2",
      "first-page": "190",
      "volume": "55",
      "author": "Hsieh J T",
      "year": "1995",
      "unstructured": "J T Hsieh, W Luo, W Song, Y Wang, D I Kleinerman, N T Van, S H Lin Cancer Res 55, 190\u2013197 (1995).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_11_2",
      "first-page": "227",
      "volume": "26",
      "author": "Lin S H",
      "year": "1999",
      "unstructured": "S H Lin, Y S Pu Semin Oncol 26, 227\u2013233 (1999).",
      "journal-title": "Semin Oncol"
    },
    {
      "key": "e_1_3_3_12_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/bbrc.1999.1443"
    },
    {
      "key": "e_1_3_3_13_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1097/00005392-199909010-00085"
    },
    {
      "key": "e_1_3_3_14_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1242/jcs.112.23.4193"
    },
    {
      "key": "e_1_3_3_15_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/(SICI)1097-4652(199704)171:1<11::AID-JCP2>3.0.CO;2-K"
    },
    {
      "key": "e_1_3_3_16_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1091/mbc.10.9.2817"
    },
    {
      "key": "e_1_3_3_17_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.89.19.9064"
    },
    {
      "key": "e_1_3_3_18_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.95.25.14821"
    },
    {
      "key": "e_1_3_3_19_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.137.1.231"
    },
    {
      "key": "e_1_3_3_20_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0959-8049(00)00062-9"
    },
    {
      "key": "e_1_3_3_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0304-3835(91)90093-W"
    },
    {
      "key": "e_1_3_3_22_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/(SICI)1096-9896(199904)187:5<567::AID-PATH288>3.0.CO;2-J"
    },
    {
      "key": "e_1_3_3_23_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.138.6.1379"
    },
    {
      "key": "e_1_3_3_24_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.cdd.4400404"
    },
    {
      "key": "e_1_3_3_25_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.273.16.9357"
    },
    {
      "key": "e_1_3_3_26_2",
      "first-page": "527",
      "volume": "1",
      "author": "Rojas M",
      "year": "1990",
      "unstructured": "M Rojas, A Fuks, C P Stanners Cell Growth Differ 1, 527\u2013533 (1990).",
      "journal-title": "Cell Growth Differ"
    },
    {
      "key": "e_1_3_3_27_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0021-9258(18)52436-4"
    },
    {
      "key": "e_1_3_3_28_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0006-291X(92)90828-9"
    },
    {
      "key": "e_1_3_3_29_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.onc.1202935"
    },
    {
      "key": "e_1_3_3_30_2",
      "first-page": "2375",
      "volume": "11",
      "author": "Kunath T",
      "year": "1995",
      "unstructured": "T Kunath, C Ordonez-Garcia, C Turbide, N Beauchemin Oncogene 11, 2375\u20132382 (1995).",
      "journal-title": "Oncogene"
    },
    {
      "key": "e_1_3_3_31_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0092-8674(95)90169-8"
    },
    {
      "key": "e_1_3_3_32_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.M109110200"
    },
    {
      "key": "e_1_3_3_33_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0014-5793(98)00222-1"
    },
    {
      "key": "e_1_3_3_34_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1182/blood.V84.1.211.211"
    },
    {
      "key": "e_1_3_3_35_2",
      "first-page": "2963",
      "volume": "55",
      "author": "Frangsmyr L",
      "year": "1995",
      "unstructured": "L Frangsmyr, V Baranov, F Prall, M M Yeung, C Wagener, S Hammarstrom Cancer Res 55, 2963\u20132967 (1995).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_36_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1083/jcb.96.4.1168"
    },
    {
      "key": "e_1_3_3_37_2",
      "first-page": "2224",
      "volume": "58",
      "author": "Sun H",
      "year": "1998",
      "unstructured": "H Sun, S A Santoro, M M Zutter Cancer Res 58, 2224\u20132233 (1998).",
      "journal-title": "Cancer Res"
    },
    {
      "key": "e_1_3_3_38_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.7531366"
    },
    {
      "key": "e_1_3_3_39_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0002-9440(10)61725-7"
    },
    {
      "key": "e_1_3_3_40_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/ncb0901-785"
    }
  ],
  "container-title": "Proceedings of the National Academy of Sciences",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://pnas.org/doi/pdf/10.1073/pnas.232711199",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2022,
        4,
        13
      ]
    ],
    "date-time": "2022-04-13T13:07:31Z",
    "timestamp": 1649855251000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://pnas.org/doi/full/10.1073/pnas.232711199"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2003,
        1,
        9
      ]
    ]
  },
  "references-count": 40,
  "journal-issue": {
    "issue": "2",
    "published-print": {
      "date-parts": [
        [
          2003,
          1,
          21
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1073/pnas.232711199"
  ],
  "URL": "http://dx.doi.org/10.1073/pnas.232711199",
  "relation": {},
  "ISSN": [
    "0027-8424",
    "1091-6490"
  ],
  "subject": [],
  "container-title-short": "Proc. Natl. Acad. Sci. U.S.A.",
  "published": {
    "date-parts": [
      [
        2003,
        1,
        9
      ]
    ]
  },
  "assertion": [
    {
      "value": "2002-09-20",
      "order": 0,
      "name": "received",
      "label": "Received",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2002-11-21",
      "order": 1,
      "name": "accepted",
      "label": "Accepted",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    },
    {
      "value": "2003-01-09",
      "order": 2,
      "name": "published",
      "label": "Published",
      "group": {
        "name": "publication_history",
        "label": "Publication History"
      }
    }
  ]
}