Trastuzumab resistance induces EMT to transform HER2+ PTEN− to a triple negative breast cancer that requires unique treatment options

Abstract

Although trastuzumab is an effective treatment in early stage HER2+ breast cancer the majority of advanced HER2+ breast cancers develop trastuzumab resistance, especially in the 40% of breast cancers with loss of PTEN. However, HER2+ breast cancer patients continue to receive trastuzumab regardless PTEN status and the consequence of therapy in these patients is unknown. We demonstrate that continued use of trastuzumab in HER2+ cells with loss of PTEN induces the epithelial-mesenchymal transition (EMT) and transform HER2+ to a triple negative breast cancer. These transformed cells exhibited mesenchymal morphology and gene expression markers, while parent HER2+ cells showed epithelial morphology and markers. The transformed cells exhibited loss of dependence on ERBB family signaling (such as HER2, HER3, HER4, BTC, HRG, EGF) and reduced estrogen and progesterone receptors. Continued use of trastuzumab in HER2+ PTEN− cells increased the frequency of cancer stem cells (CSCs) and metastasis potential. Strikingly, parental HER2+ cells and transformed resistant cells respond to treatment differently. Transformed resistant cells were sensitive to chemical probe (sulforaphane) through inhibition of IL-6/STAT3/NF-κB positive feedback loop whereas parental HER2+ cells did not respond. This data suggests that trastuzumab resistance in HER2+ PTEN− breast cancer induces EMT and subtype switching, which requires unique treatment options.

Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer

“…Our previous studies have shown that continued use of trastuzumab in PTEN-deficient breast cancer cells induced the EMT in bulk cell lines, increased BCSC characteristics, and transformed HER2+ to a triple negative phenotype [10, 14]. However, recent evidence suggests BCSCs may exist in two distinct states, mesenchymal-like (CD44+/CD24-) and epithelial-like (ALDH+), which can interconvert in breast cancer [15].…”

“…Our most recent study has shown that continued use of trastuzumab in PTEN-deficient breast cancer cells induced the EMT, expands breast cancer stem cells (BCSCs)[10], and transform HER2+ to a trastuzumab-resistant triple negative phenotype [14]. These transformed cancer cells show distinct sensitivity to the small molecule sulforaphane, which suggests that different treatment options need to be developed for PTEN-deficient trastuzumab-resistant breast cancer.…”

“…The unique properties of self-renewal and differentiation of the BCSC population is suspected to be responsible for drug resistance [11–13]. Our recent study showed that continued use of trastuzumab in PTEN-deficient HER2+ breast cancer induces the epithelial-mesenchymal transition (EMT) and transform HER2+ to a triple negative like breast cancer, which requires unique treatment options [14]. Liu et.al.…”

Identification of New Tumor Suppressor Genes in Triple-Negative Breast Cancer

“…To better understand the genetic forces driving TNBC, we performed a SB transposon mutagenesis screen in Pten-mutant mice. Pten was used as a sensitizing mutation in the screen because loss of PTEN has been implicated in breast cancer progression, is clonally selected in TNBC, and favors the activation of the EMT pathway to promote metastasis (7,25).…”

Phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as therapeutic targets in breast cancer

“…Ning et al 130 showed that the inhibition of autophagy induced by PTEN loss led to intrinsic BCa resistance to trastuzumab therapy. Burnett et al 131 reported that trastuzumab resistance stimulates EMT to transform HER2 (+) PTEN (−) to a TN-BCa that necessitates unique treatment options. Wang et al 132 reported that targeted PTEN deletion plus p53-R270H mutation in mouse mammary epithelium stimulates aggressive claudin-low and basal-like BCa.…”