Heat shock protein Hsp72 plays an essential role in Her2-induced mammary tumorigenesis

Abstract

The major heat shock protein Hsp72 is expressed at elevated levels in many human cancers and its expression correlates with tumor progression. Here we investigated the role of Hsp72 in Her2 oncogene-induced neoplastic transformation and tumorigenesis. Expression of Her2 in untransformed MCF10A mammary epithelial cells caused transformation, as judged by foci formation in culture and tumorigenesis in xenografts. However, expression of Her2 in Hsp72-depleted cells failed to induce transformation. The anti-tumorigenic effects of Hsp72 downregulation were associated with cellular senescence due to accumulation of p21 and depletion of survivin. Accordingly, either knockdown of p21 or expression of survivin reversed this senescence process. Further, we developed an animal model of Hsp72-dependent breast cancer associated with expression of Her2. Knockout of Hsp72 almost completely suppressed tumorigenesis in the MMTVneu breast cancer mouse model. In young Hsp72 KO mice, expression of Her2 instead of mammary tissue hyperplasia led to suppression of duct development and blocked alveolar budding. These effects were due to massive cell senescence in mammary tissue, which was associated with upregulation of p21 and downregulation of survivin. Therefore Hsp72 plays an essential role in Her2-induced tumorigenesis by regulating oncogene-induced senescence pathways.

Hsf1 in Her2-positive Breast Cancer

“…2). Therefore, Hsf1 KO prevented Her2-induced tissue hyperplasia, possibly by aggravating senescence, similar to what we have found recently with NeuT-induced mammary tumors in the Hsp72 knockout mouse model [6]. (median tumor appearance in this strain was about 55 weeks), indicating that one copy of the Hsf1 gene is sufficient to support mammary tumor emergence induced by Her2/NeuT (Fig.…”

Proteotoxicity is not the reason for the dependence of cancer cells on the major chaperone Hsp70

“…[10][11][12] Accordingly, depletion of Hsp70 in cancer cells lines led to induction of the cell cycle inhibitor p21 and triggered senescence and permanent growth arrest. [10][11][12] Potentially, these effects could be associated with triggering proteotoxic stress, for example due to aneuploidy-related protein imbalance. The major prediction of this model is that the overall chaperone capacity of cancer cells is limited due to the high levels of abnormal proteins, and thus depletion of Hsp70 should trigger proteotoxic stress.…”

“…As noted previously, these effects were specific to transformed cells and were not seen in untransformed breast epithelial MCF10A cells. 10,11 As readout of proteotoxicity, we determined the levels of ubiquitinated proteins. Contrary to the predictions of the hypothesis, depletion of Hsp70 did not significantly alter levels of ubiquitinated proteins (Fig.…”

“…[6][7][8][9] Interestingly, we reported that it is enough to knockout just one of the major chaperones, Hsp70, to similarly block cancer development in the model of Her2-postive breast cancer. 10 Overall, it was uncovered that Hsf1 and Hsp70 are critical for the survival and growth of many types of cancer cells, but are dispensable for normal cells. [10][11][12] For example, depletion of either Hsp70 or Hsf1 in untransformed breast epithelial line MCF10A is not harmful.…”

“…10 Overall, it was uncovered that Hsf1 and Hsp70 are critical for the survival and growth of many types of cancer cells, but are dispensable for normal cells. [10][11][12] For example, depletion of either Hsp70 or Hsf1 in untransformed breast epithelial line MCF10A is not harmful. However, similar depletion in cells transformed with Her2 or PIK3CA oncogenes leads to growth arrest and overall senescence.…”