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Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract

Nature Medicine volume 11, pages 531–537 (2005)Cite this article

Abstract

Although epithelial ovarian cancers (EOCs) have been thought to arise from the simple epithelium lining the ovarian surface or inclusion cysts, the major subtypes of EOCs show morphologic features that resemble those of the müllerian duct–derived epithelia of the reproductive tract. We found that HOX genes, which normally regulate müllerian duct differentiation, are not expressed in normal ovarian surface epithelium (OSE), but are expressed in different EOC subtypes according to the pattern of müllerian-like differentiation of these cancers. Ectopic expression of Hoxa9 in tumorigenic mouse OSE cells gave rise to papillary tumors resembling serous EOCs. In contrast, Hoxa10 and Hoxa11 induced morphogenesis of endometrioid-like and mucinous-like EOCs, respectively. Hoxa7 showed no lineage specificity, but promoted the abilities of Hoxa9, Hoxa10 and Hoxa11 to induce differentiation along their respective pathways. Therefore, inappropriate activation of a molecular program that controls patterning of the reproductive tract could explain the morphologic heterogeneity of EOCs and their assumption of müllerian-like features.

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Figure 1: Spatially restricted HOX expression in the reproductive tract.
Figure 2: EOC subtype–specific HOX expression.
Figure 3: Morphologic alterations induced by HOX genes.
Figure 4: Differential expression of molecular markers in MOSEC tumors.
Figure 5: Induction of low-grade features by Hoxa7 in MOSEC tumors.

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Acknowledgements

We thank J. Hung and K. Head for technical assistance, R. Broaddus for providing additional tissue specimens, G. Mills, Y. Lu, R. Bast and R. Behringer (University of Texas M.D. Anderson Cancer Center) for discussions, and N. Auersperg (University of British Columbia) for IOSE-29 cells. This work was supported by US Department of the Army Award DAMD 17-03-1-0219 (H.N.); by US National Institutes of Health/National Cancer Institute Grants R21 CA102108 (H.N), R01 CA101826 (H.N.), P01 CA64602 (J.L.); by a University of Texas M.D. Anderson Cancer Center Institutional Research Grant (H.N.); by an award from Cancer Fighters of Houston (H.N.); by American Cancer Society Grant RSG-04-028-1-CCE (J.L.).

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  1. Wenjun Cheng

    Present address: Department of Gynecologic Oncology, Jiangsu Cancer Hospital & Institute, 42 Baiziting Road, Nanjing, Jiangsu, 210009, P.R. China

Authors and Affiliations

  1. Department of Molecular Therapeutics, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 184, Houston, 77030, Texas, USA

    Wenjun Cheng, Hiroyuki Yoshida & Honami Naora

  2. Department of Pathology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 85, Houston, 77030, Texas, USA

    Jinsong Liu & Daniel Rosen

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Correspondence to Honami Naora.

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Supplementary information

Supplementary Fig. 1

RT-PCR analysis of HOX expression in normal reproductive tract tissues and in EOCs. (PDF 103 kb)

Supplementary Fig. 2

Specificity of HOX antibodies determined by siRNA knockdown. (PDF 332 kb)

Supplementary Fig. 3

Ectopic HOX expression in stably transfected MOSEC cell lines. (PDF 143 kb)

Supplementary Fig. 4

HOX expression in tumors dervied from stably transfected MOSEC cells. (PDF 399 kb)

Supplementary Fig. 5

Morphologic alterations induced by HOXA7 in SKOV3 cells. (PDF 144 kb)

Supplementary Methods (PDF 21 kb)

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Cheng, W., Liu, J., Yoshida, H. et al. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract. Nat Med 11, 531–537 (2005). https://doi.org/10.1038/nm1230

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