[HTML][HTML] Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

BD Lehmann, JA Bauer, X Chen… - The Journal of …, 2011 - Am Soc Clin Investig
BD Lehmann, JA Bauer, X Chen, ME Sanders, AB Chakravarthy, Y Shyr, JA Pietenpol
The Journal of clinical investigation, 2011Am Soc Clin Investig
Intratumor heterogeneity is a major clinical problem because tumor cell subtypes display
variable sensitivity to therapeutics and may play different roles in progression. We previously
characterized 2 cell populations in human breast tumors with distinct properties: CD44+
CD24–cells that have stem cell-like characteristics, and CD44–CD24+ cells that resemble
more differentiated breast cancer cells. Here we identified 15 genes required for cell growth
or proliferation in CD44+ CD24–human breast cancer cells in a large-scale loss-of-function …
Abstract
Intratumor heterogeneity is a major clinical problem because tumor cell subtypes display variable sensitivity to therapeutics and may play different roles in progression. We previously characterized 2 cell populations in human breast tumors with distinct properties: CD44+ CD24–cells that have stem cell-like characteristics, and CD44–CD24+ cells that resemble more differentiated breast cancer cells. Here we identified 15 genes required for cell growth or proliferation in CD44+ CD24–human breast cancer cells in a large-scale loss-of-function screen and found that inhibition of several of these (IL6, PTGIS, HAS1, CXCL3, and PFKFB3) reduced Stat3 activation. We found that the IL-6/JAK2/Stat3 pathway was preferentially active in CD44+ CD24–breast cancer cells compared with other tumor cell types, and inhibition of JAK2 decreased their number and blocked growth of xenografts. Our results highlight the differences between distinct breast cancer cell types and identify targets such as JAK2 and Stat3 that may lead to more specific and effective breast cancer therapies.
The Journal of Clinical Investigation