Investigation of hormone signalling and breast epithelial hierarchy in women at a high risk of cancer

UoM administered thesis: Phd

  • Authors:
  • Alice Greenhalgh

Abstract

Estrogen, progesterone and prolactin help control human breast development. Hormonal signalling is a known breast cancer risk factor, but little is known about how increased risk affects the hormonal signalling pathways and the epithelial hierarchy of the human breast. In this study we used human breast tissue samples from women at either high risk or normal risk of developing breast cancer. Immunostaining was performed for Estrogen Receptor (ER), Progesterone Receptor (PR), proliferation (KI67) and luminal progenitors (SOX9/C-KIT). High risk women had significantly increased expression of ER, PR and KI67 as well an increased number of luminal progenitor cells. We assessed the effects of progesterone using tissues from high risk women recruited in the BCAPPS study who received the antiprogestin, ulipristal acetate (UA) for 3 months. Analysis of BCAPPS samples showed UA significantly decreased proliferation. We used FACS to sort breast tissue microstructures from normal and high risk women into mature luminal, luminal progenitor, basal and stromal populations, from which RNA was extracted and RT-PCR/RNA sequencing were performed. Gene expression analysis confirmed we had successfully sorted breast cells into 3 epithelial subpopulations (n=22) and principal component analysis indicated that subpopulations cluster together according to risk. RNA sequencing identified novel pathways and targets for future breast cancer prevention, such as IL8 and NFkB signalling. In conclusion, we found high risk women have increased hormone signalling, increased progenitors and increased proliferation. We propose that high risk genes lead to deregulated hormone signalling pathways, allowing the progenitor cells to divide which may promote tumour formation in the luminal layer of the breast. There are several pathways that may enable this, for example the NFkB and IL8 pathways. We recommend that future prevention methods should target pathways, such as NFkB and IL8, stopping aberrant luminal cell division that may lead to breast cancer in high risk women.

Details

Original languageEnglish
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Award date1 Aug 2019