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Proc Natl Acad Sci U S A. Apr 25, 1995; 92(9): 3687–3691.
PMCID: PMC42026

Immortalization of distinct human mammary epithelial cell types by human papilloma virus 16 E6 or E7.

Abstract

Multiple mammary epithelial cell (MEC) types are observed both in mammary ducts in vivo and in primary cultures in vitro; however, the oncogenic potential of different cell types remains unknown. Here, we used human papilloma virus 16 E6 and E7 oncogenes, which target p53 and Rb tumor suppressor proteins, respectively, to immortalize MECs present in early or late passages of human mammary tissue-derived cultures or in milk. One MEC subtype was exclusively immortalized by E6; such cells predominated in late-passage cultures but were rare at early passages and apparently absent in milk. Surprisingly, a second cell type, present only in early-passage tissue-derived cultures, was fully immortalized by E7 alone. A third cell type, observed in tissue-derived cultures and in milk, showed a substantial extension of life span with E7 but eventually senesced. Finally, both E6 and E7 were required to fully immortalize milk-derived MECs and a large proportion of MECs in early-passage tissue-derived cultures, suggesting the presence of another discrete subpopulation. Identification of MECs with distinct susceptibilities to p53- and Rb-targeting human papillomavirus oncogenes raises the possibility that these cells may serve as precursors for different forms of breast cancer.

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  • Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982 Nov;31(1):11–24. [PubMed]
  • Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982 Nov;31(1):11–24. [PubMed]
  • Trask DK, Band V, Zajchowski DA, Yaswen P, Suh T, Sager R. Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2319–2323. [PMC free article] [PubMed]
  • Bartek J, Bartkova J, Kyprianou N, Lalani EN, Staskova Z, Shearer M, Chang S, Taylor-Papadimitriou J. Efficient immortalization of luminal epithelial cells from human mammary gland by introduction of simian virus 40 large tumor antigen with a recombinant retrovirus. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3520–3524. [PMC free article] [PubMed]
  • Band V, Sager R. Distinctive traits of normal and tumor-derived human mammary epithelial cells expressed in a medium that supports long-term growth of both cell types. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1249–1253. [PMC free article] [PubMed]
  • Band V, Sager R. Distinctive traits of normal and tumor-derived human mammary epithelial cells expressed in a medium that supports long-term growth of both cell types. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1249–1253. [PMC free article] [PubMed]
  • Band V, De Caprio JA, Delmolino L, Kulesa V, Sager R. Loss of p53 protein in human papillomavirus type 16 E6-immortalized human mammary epithelial cells. J Virol. 1991 Dec;65(12):6671–6676. [PMC free article] [PubMed]
  • Band V, De Caprio JA, Delmolino L, Kulesa V, Sager R. Loss of p53 protein in human papillomavirus type 16 E6-immortalized human mammary epithelial cells. J Virol. 1991 Dec;65(12):6671–6676. [PMC free article] [PubMed]
  • Band V, Dalal S, Delmolino L, Androphy EJ. Enhanced degradation of p53 protein in HPV-6 and BPV-1 E6-immortalized human mammary epithelial cells. EMBO J. 1993 May;12(5):1847–1852. [PMC free article] [PubMed]
  • Band V, Dalal S, Delmolino L, Androphy EJ. Enhanced degradation of p53 protein in HPV-6 and BPV-1 E6-immortalized human mammary epithelial cells. EMBO J. 1993 May;12(5):1847–1852. [PMC free article] [PubMed]
  • Band V, Zajchowski D, Kulesa V, Sager R. Human papilloma virus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements. Proc Natl Acad Sci U S A. 1990 Jan;87(1):463–467. [PMC free article] [PubMed]
  • Band V, Zajchowski D, Kulesa V, Sager R. Human papilloma virus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements. Proc Natl Acad Sci U S A. 1990 Jan;87(1):463–467. [PMC free article] [PubMed]
  • Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol. 1989 Oct;63(10):4417–4421. [PMC free article] [PubMed]
  • Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol. 1989 Oct;63(10):4417–4421. [PMC free article] [PubMed]
  • Halbert CL, Demers GW, Galloway DA. The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells. J Virol. 1992 Apr;66(4):2125–2134. [PMC free article] [PubMed]
  • Halbert CL, Demers GW, Galloway DA. The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells. J Virol. 1992 Apr;66(4):2125–2134. [PMC free article] [PubMed]
  • Androphy EJ, Hubbert NL, Schiller JT, Lowy DR. Identification of the HPV-16 E6 protein from transformed mouse cells and human cervical carcinoma cell lines. EMBO J. 1987 Apr;6(4):989–992. [PMC free article] [PubMed]
  • Androphy EJ, Hubbert NL, Schiller JT, Lowy DR. Identification of the HPV-16 E6 protein from transformed mouse cells and human cervical carcinoma cell lines. EMBO J. 1987 Apr;6(4):989–992. [PMC free article] [PubMed]
  • Wazer DE, Chu Q, Liu XL, Gao Q, Safaii H, Band V. Loss of p53 protein during radiation transformation of primary human mammary epithelial cells. Mol Cell Biol. 1994 Apr;14(4):2468–2478. [PMC free article] [PubMed]
  • Wazer DE, Chu Q, Liu XL, Gao Q, Safaii H, Band V. Loss of p53 protein during radiation transformation of primary human mammary epithelial cells. Mol Cell Biol. 1994 Apr;14(4):2468–2478. [PMC free article] [PubMed]
  • Liu XL, Band H, Gao Q, Wazer DE, Chu Q, Band V. Tumor cell-specific loss of p53 protein in a unique in vitro model of human breast tumor progression. Carcinogenesis. 1994 Sep;15(9):1969–1973. [PubMed]
  • Liu XL, Band H, Gao Q, Wazer DE, Chu Q, Band V. Tumor cell-specific loss of p53 protein in a unique in vitro model of human breast tumor progression. Carcinogenesis. 1994 Sep;15(9):1969–1973. [PubMed]
  • el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994 Mar 1;54(5):1169–1174. [PubMed]
  • el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994 Mar 1;54(5):1169–1174. [PubMed]
  • Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 1993 Apr 29;362(6423):857–860. [PubMed]
  • Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 1993 Apr 29;362(6423):857–860. [PubMed]
  • Kaelin WG, Jr, Pallas DC, DeCaprio JA, Kaye FJ, Livingston DM. Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product. Cell. 1991 Feb 8;64(3):521–532. [PubMed]
  • Moscow JA, Fairchild CR, Madden MJ, Ransom DT, Wieand HS, O'Brien EE, Poplack DG, Cossman J, Myers CE, Cowan KH. Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors. Cancer Res. 1989 Mar 15;49(6):1422–1428. [PubMed]
  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990 Dec 21;63(6):1129–1136. [PubMed]
  • Münger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J. 1989 Dec 20;8(13):4099–4105. [PMC free article] [PubMed]
  • Demers GW, Foster SA, Halbert CL, Galloway DA. Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4382–4386. [PMC free article] [PubMed]
  • Slebos RJ, Lee MH, Plunkett BS, Kessis TD, Williams BO, Jacks T, Hedrick L, Kastan MB, Cho KR. p53-dependent G1 arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5320–5324. [PMC free article] [PubMed]
  • Hickman ES, Picksley SM, Vousden KH. Cells expressing HPV16 E7 continue cell cycle progression following DNA damage induced p53 activation. Oncogene. 1994 Aug;9(8):2177–2181. [PubMed]
  • DeCaprio JA, Ludlow JW, Lynch D, Furukawa Y, Griffin J, Piwnica-Worms H, Huang CM, Livingston DM. The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell. 1989 Sep 22;58(6):1085–1095. [PubMed]

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