Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Luminal breast cancers (ER(+)PR(+)) respond to hormone therapies, while basal-like triple-negative cancers (ER(-)PR(-)CK5(+)) require chemotherapy.
• A significant proportion of ER(+)PR(+) breast cancers harbor an ER(-)PR(-)CK5(+) subpopulation, termed 'luminobasal' cells.

Purpose of the Study:

• To investigate the plasticity of ER(+)PR(+) breast cancers and the emergence of hormone-resistant subpopulations under therapy.
• To elucidate the mechanisms regulating the expansion of luminobasal cells and identify potential therapeutic targets.

Main Methods:

• Generation of ER(+)PR(+) luminal cell lines with varying proportions of luminobasal cells.
• Analysis of molecular and biological properties of these cell lines under different hormonal conditions and therapies.
• Investigating the role of Notch1 signaling in luminobasal cell expansion and its modulation by γ-secretase inhibitors.

Main Results:

• Luminobasal cells expand in ER(+)PR(+) breast cancers during antiestrogen or estrogen withdrawal therapies.
• The emergent hormone-resistant cells exhibit a phenotype and gene signature consistent with basal-like and claudin-low breast cancer.
• Luminobasal cell expansion is regulated by Notch1 signaling and can be inhibited by γ-secretase inhibitors.

Conclusions:

• ER(+)PR(+) luminal breast cancers possess inherent plasticity, allowing the outgrowth of hormone-resistant basal-like disease in response to treatment.
• This treatment-induced resistance can be prevented by combining endocrine therapies with Notch pathway inhibitors.