Changed lineage composition, an event regulated by progesterone, occurs early in breast carcinogenesis — ASN Events

Changed lineage composition, an event regulated by progesterone, occurs early in breast carcinogenesis (#299)

Heidi Hilton 1 , Nicole Santucci 1 , Audrey Silvestri 1 , Silke Kantimm 1 , Lily Huschtscha 2 , Dinny Graham 1 , Christine Clarke 1
  1. Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia
  2. Childrens Medical Research Institute, Sydney, NSW, Australia

The co-ordinated development of stem/progenitor cells into luminal and basal/myoepithelial cells, and maintenance of the relative proportion of these cell types, is fundamentally important for normal breast morphogenesis. The steroid hormones, progesterone (P) and estrogen (E),are critical in driving this morphogenesis, yet have also been shown to be major drivers of breast cancer risk. We demonstrated that P treatment increases proliferation and expands the human breast bipotent progenitor cell compartment. As changes in cell type composition is one of the hallmark features of breast cancer progression, and most breast tumors contain only luminal cells, we further investigated the effect of P on lineage composition of human breast cells. We exposed primary breast cultures grown in 3D culture to treatment with E and/or P followed by quantitation of acini numbers which contained only luminal, only basal/myoepithelial, or both cell types. Each hormone treatment regimen increased the proportion of dual lineage acini, and was most pronounced with P only treatment, consistent with there being an increase in bipotent progenitor cell number. This was supported by flow cytometry analysis, which surprisingly revealed an increase in basal/myoepithelial cell numbers with P treatment, but not with E or E+P treatment. We then investigated changes in cellular composition by quantitating luminal cell numbers relative to surrounding basal/myoepithelial cells in a panel of normal and pre-invasive breast tissue samples, and correlated these findings with proliferation in the same lesions. We showed that changed lineage composition correlated with increased proliferation, and was an early event in breast carcinogenesis. Therefore, as P stimulates progenitors and is a major driver of breast cancer risk, and changed lineage composition is an early event in breast carcinogenesis, it is important to now determine whether modulation of cell fate determination by aberrant P signaling results in increased susceptibility to breast carcinogenesis.

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