Effect of Cellular Senescence on the Growth of HER2-Positive Breast Cancers

+Author Affiliations

Affiliations of authors: Preclinical Research (MZF, BM, RV, ALG, ME, JV, JA) and Clinical Research Programs (ITR), Vall d’Hebron Institute of Oncology, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain (JA).

Correspondence to: Joaquín Arribas, PhD, Psg. Vall d’Hebron 119-129, Barcelona 08035, Spain (e-mail: jarribas@vhio.net).

Received August 12, 2014.
Revision received December 4, 2014.
Accepted January 20, 2015.

Abstract

Background: Oncogene-induced senescence (OIS) is a tumor suppressor mechanism. However, senescent cells remain viable and display a distinct secretome (also known as senescence-associated secretory phenotype [SASP] or senescence messaging secretome, [SMS]) that, paradoxically, includes protumorigenic factors. OIS can be triggered by ectopic overexpression of HER2, a receptor tyrosine kinase and the driving oncogene in a subtype of human breast cancer. However, cellular senescence has not been characterized in HER2-positive tumors.

Methods: Using an approach based on their inability to proliferate, we isolated naturally occurring senescent cells from a variety of tumor models including HER2-positive cells, transgenic mice (n = 3), and patient-derived xenografts (PDXs) (n = 6 mice per group from one PDX derived from one patient). Using different biochemical and cell biological techniques, we characterized the secretome of these senescent cells. All statistical tests were two-sided.

Results: We found that senescent cells arise constantly in different models of advanced breast cancers overexpressing HER2 and constitute approximately 5% of tumor cells. In these models, IL-6 and other cytokines were expressed mainly, if not exclusively, by the naturally occurring senescent cells (95.1% and 45.0% of HCC1954 cells and cells from a HER2-positive PDX expressing a senescent marker expressed IL-6, respectively). Furthermore, inhibition of IL-6 impaired the growth of the HER2-positive PDX (mean tumor volume at day 101, control vs anti–huIL-6 treated, 332.2mm³ [95% confidence interval {CI} = 216.6 to 449.8] vs 114.4mm³ [95% CI = 12.79 to 216.0], P = .005).

Conclusions: Senescent cells can contribute to the growth of tumors by providing cytokines not expressed by proliferating cells, but required by these to thrive.