Tamoxifen-stimulated growth of breast cancer due to p21 loss

Abstract

Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclindependent kinase inhibitory property results in hyperphosphorylation of estrogen receptor-␣, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers.estrogen receptor ͉ p21 knockout ͉ drug resistance ͉ selective estrogen receptor modulator

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

“…3B). Interestingly, MACROD2 overexpressing cell lines were growth-stimulated by tamoxifen, similar to prior reports that tamoxifen can often act as an ER agonist when resistance occurs (10). To definitively demonstrate that MACROD2 was mediating tamoxifen resistance along with tamoxifen-stimulated growth, TamR and MACROD2 overexpressing cell lines were exposed to estrogen, tamoxifen, or both.…”

“…CDK inhibitor p21 could mediate resistance to this SERM (10). We reasoned that additional tamoxifen resistant clones, which retained p21 expression, acquired resistance through additional mechanisms and that common copy number (CN) alterations within these clones could help identify molecular mediators of this phenotype.…”

“…In part, this is due to the heterogeneous nature of breast cancers, resulting in multiple mechanisms of resistance. For example, past studies have demonstrated that tamoxifen resistance is mediated by differential expression of nuclear hormone receptor coregulators (2, 3), growth factor signaling crosstalk (4-7), regulation of microRNAs (8), cyclin dependent kinases (CKDs) (9), CDK inhibitors (10,11), and more recently, acquired somatic mutations and alterations in ER (12)(13)(14)(15)(16)(17). Further insight into the molecular mediators of tamoxifen and hormone therapy resistance would have great impact on the ability to target genes and pathways that could overcome drug resistance and lead to improved clinical outcomes.…”

Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression

“…BHPI does not inhibit protein synthesis in ERα-negative MCF-10A breast cells, but gains the ability to inhibit protein synthesis when ERα is stably expressed in isogenic MCF10A ER IN9 cells (Fig. 3B) (21). Notably, BHPI loses the ability to inhibit protein synthesis when ERα in the stably transfected cells is knocked down with siRNA ( Fig.…”

Age at first childbirth and oral contraceptive use are associated with risk of androgen receptor-negative breast cancer: the Malmö Diet and Cancer Cohort

“…AR has also been suggested to interact with cell cycle checkpoint protein p21, which is involved in epidermal growth factor signaling (14). Further, AR expression may be associated with response to tamoxifen (TAM) (15). The significance of AR expression in ER negative (ER -) breast cancer and triple negative breast cancer (TNBC) has been contradictory.…”