Mislocalization of p27 to the cytoplasm of breast cancer cells confers resistance to anti-HER2 targeted therapy

Abstract

As a cell cycle inhibitor and tumor suppressor, p27 is frequently misregulated in human cancers. Increased degradation is the most common mechanism of misregulation, however in some cancers, p27 is mislocalized from its cell cycle inhibitory location in the nucleus, to the cytoplasm. In normal cells cytoplasmic p27 has functions that are distinct from its cell cycle-regulatory nuclear functions. Therefore, an important question is whether localization of p27 to the cytoplasm in tumor cells is primarily a mechanism for cancelling its inhibitory effect on cell proliferation, or whether cytoplasmic p27 has more direct oncogenic actions. To study p27 mislocalization in human cancers we screened a panel of common breast cancer cell lines. We observed that p27 accumulated in the cytoplasm exclusively in cell lines that are Her2+. To address the significance of p27 mislocalization in Her2+ breast cancer cells we interrogated the cellular response to the dual-Her2/EGFR kinase inhibitor, lapatinib. Knockdown of p27 using shRNA sensitized Her2+ cells to lapatinib-induced apoptosis. Moreover, expression of a constitutively cytoplasmic form of p27 (p27ΔNLS) reversed the lapatinib-induced apoptosis, suggesting that cytoplasmic p27 contributed to lapatinib resistance in Her2+ breast cancer cells by suppressing apoptosis. Our results suggest that p27 localization may be useful as a predictive biomarker of therapeutic response in patients with Her2+ breast cancers.

Regulating the stability and localization of CDK inhibitor p27Kip1 via CSN6-COP1 axis

“…p27 is a nuclear protein with a tumor suppressive role, but oncogenic signal-mediated cytoplasmic retention and nuclear export of p27 results in enhanced oncogenic activity 28,38 or drug resistance. 26 Once translocated to the cytoplasm, p27 will gain the function of promoting cancer cell migration and invasiveness. 38 Thus, cytosolic p27 has a metastasis promoting function opposite to the tumor suppressor role of nuclear p27.…”

“…17 p27 is regulated by many oncogenic signals for facilitating cell cycle progression. [18][19][20][21][22][23][24][25][26] Protein levels of p27 are tightly controlled for cell cycle progression, 16,17,27 and p27 levels are positively regulated by the activity of many tumor suppressors. 22,28 As a negative regulator of the cell cycle, p27 is also functioning like a tumor suppressor.…”

Targeting intrinsically disordered proteins involved in cancer

“…This regulation is incorrectly activated in chronic myelogenous leukemia and breast cancer [50,51]. In addition, phosphorylation of this domain at a threonine is related to increased metastatic processes and cell migration [52,53]. The p27-KID is an IDP [54,55].…”

Epithelial morphological reversion drives Profilin-1-induced elevation of p27kip1in mesenchymal triple-negative human breast cancer cells through AMP-activated protein kinase activation

“…Additionally, a recent study has shown that cytoplasmic mislocalization of p27 in HER2-positive breast cancer cells causes resistance to lapatinib, a dual EGFR-HER2 inhibitor. 47 Therefore, it will be also interesting to determine in the future whether Pfn1 expression has any effect on p27 localization and therapeutic resistance in HER2-positive breast cancer cells. Finally, our finding that Pfn1 overexpression stimulates AMPK activation has much broader implications in the context of cancer beyond and above p27 regulation.…”