NFk B drives stemness and resistance to therapy in ER+HER2- breast cancer

Volume 11, Number 19 of @Oncotarget reported that RANK pathway affects the expression of cell cycle regulators and decreases sensitivity to fulvestrant of estrogen receptor-positive /HER2- breast cancer cells, MCF-7 and T47D.

These results suggest that ER+HER2- RANK-positive cells may constitute an important reservoir of slow cycling, therapy-resistance cancer cells; and that RANK pathway activation is deleterious in all ER+HER2- breast cancer cells, independently of RANK levels.

Dr. Sandra Casimiro from The Luis Costa Laborator at The Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa in Lisboa Portuga said, "Breast cancer is responsible for over 600,000 deaths per year worldwide, the vast majority due to cancer spread into distant organs."

"Breast cancer is responsible for over 600,000 deaths per year worldwide, the vast majority due to cancer spread into distant organs."

- Dr. Sandra Casimiro, The Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa

Overexpression of RANK in normal HR-negative MCF10A mammary cells induces stemness and transformation features, namely mammary gland reconstitution, epithelial-mesenchymal transition, increased migration, and anchorage-independent growth; interfering with mammary cell commitment and contributing to breast carcinogenesis.

In clinical samples, RANK was found to be expressed by different solid tumors, and RANK expression emerged as a predictive marker of breast cancer bone metastasis occurrence and shorter disease-free survival, being correlated with high grade and negative HR status.

Figure 1: RANK overexpression is associated with altered cell cycle regulators and induced resistance to fulvestrant. (A) RT-qPCR of RANK in parental and RANK OE cell lines (n = 3). (B) Flow cytometry of RANK in parental and RANK OE cell lines. (C, D, E) Downstream targets of RANK were analyzed by western blot upon stimulus with 1 μg/ml RANKL for the indicated time points. β-Actin was used as loading control. (F) Doubling time was quantified under standard conditions, and calculated using exponential growth equation with least squares regression fitting model (n = 3). (G) Western blot of ER with β-Actin as loading control. (H) Cell viability was measured after 5 days of culture in steroids-depleted medium +/– 10 nM β-estradiol (n = 3). (I) Western blot analysis of cell cycle-related proteins with β-Actin as loading control. (J) Cell viability was measured 7 days after exposure to tamoxifen or fulvestrant, with medium replacement every 48 h. (n = 3). (K) Representative western blot of down-stream target of fulvestrant (ER) with β-Actin as loading control (n = 3). FiJi was used to obtain the best contrast for western blot band visualization, and background was removed for band densitometry analysis. Results are presented as the mean ± SEM. ^*p < 0.05, ^**p < 0.01, ^***p < 0.001.

In preclinical studies, it was shown that RANKL triggers the migration of RANK-positive human epithelial cancer cells; and RANK overexpression in triple-negative breast cancer cells was sufficient to confer a significantly greater metastatic growth rate in the bone, by inducing the expression of matrix metalloproteinases and other genes previously defined as part of a bone metastasis gene signature.

Despite evidence of heterogeneous RANK expression amongst breast tumors, the implication of RANK expression in HR-positive breast cancers has remained elusive.

The Casimiroour Research Team concluded in their Oncotarget Research Article that "results demonstrate that ER+ RANK-positive cells may drive resistance to chemotherapy and HT and contribute to metastization; and pave the way to study the effectiveness of RANK pathway inhibition, as a way to improve ER+HER2- breast cancer outcomes."

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DOI - https://doi.org/10.18632/oncotarget.27576

Full text - https://www.oncotarget.com/article/27576/text/

Correspondence to - Sandra Casimiro - scasimiro@medicina.ulisboa.pt

Keywords - RANKL-RANK pathway, ER+ breast cancer, resistance to chemo and hormone therapy, stemness, metastization

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