Suzuki, Rami Noriko; (2003) Differentiation of transformed and non-transformed human mammary luminal epithelial cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Differentiation and its therapeutic potential were examined in the context of breast cancer. First, hormonal induction of differentiation was investigated in vivo using human breast tissues obtained at the 12th, 15th and 18th weeks of pregnancy. Multiple immunofluorescence labelling for markers of proliferation and markers of differentiation demonstrated that human mammary luminal epithelial cells (HMLEC) were capable of proliferation when they were phenotypically and functionally differentiated. Second, pharmacological induction of differentiation was investigated in vitro using a longitudinal model of differentiation. This model was derived from a single parental line that represents immortalised but non-transformed HMLEC and consists of its transformed and control variants. Unlike horizontal models of cell lines obtained from different individuals, the longitudinal model allowed direct comparisons between transformed and non-transformed phenotypes as well as cause-and-effect correlation with a single oncogene such as ErbB2 and ras. The present study conducted immunofluorescence labelling analysis to ensure that the cell lines utilised in the model exhibited stable and expected phenotypes. Pharmacological agents were then examined for their growth inhibitory effects. It was demonstrated that TNF? selectively inhibited the growth of ErbB2 over-expressing variants. Molecular investigations revealed that TNF[alpha] down-regulated the transforming oncogene ErbB2 at both the mRNA and protein levels. This was accompanied by the down-regulations of p21 and p53 at the mRNA level. In summary, while differentiation does not coincide with loss of proliferative potential, certain pharmacological interventions can selectively inhibit the growth of transformed cells. Such effects can be accompanied by the down-regulation of transformation-associated genes. The in vitro model of breast cancer established in the present study provides a useful tool for further screening of pharmacological agents and studying the modes of drug actions.

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